Somatostatin receptor antagonists and glucose control or hypoglycemia

ABSTRACT

The present disclosure provides methods and uses for controlling tight blood glucose levels in a subject comprising administering an effective amount of a somatostatin inhibitor. The present disclosure provides methods and uses for treating or preventing hypoglycemia in a subject comprising administering an effective amount of a somatostatin inhibitor.

This application claims the benefit under 35 USC §119(e) of U.S.provisional application No. 60/890,965 filed Feb. 21, 2007.

FIELD OF THE INVENTION

The present disclosure relates to controlling tight blood glucose levelsin an insulin-dependent diabetic subject. In particular, the disclosurerelates to the treatment or prevention of insulin-induced hypoglycemiain diabetic subjects. The disclosure also relates to the treatment andprevention of idiopathic hypoglycemia or hypoglycemia resulting from aninsulinoma in a subject in need thereof. In particular, the disclosurerelates to methods and uses of somatostatin inhibitors to increase theglucagon and cortisol response, but may also apply to other hormones inpatients that suffer from defective counterregulation.

BACKGROUND OF THE INVENTION

The main characteristic of diabetes is hyperglycemia. Chronichyperglycemia induces severe complications of diabetes: retinopathy,cataracts, peripheral neuropathy, nephropathy, and vascular angiopathy.It is also a major health problem such that the rate of morbidity andmortality of diabetes is third greatest after cancer and cardiovasculardisease. It is important to note that diabetic patients have a muchhigher incidence of cardiovascular disease than non-diabetics. It wasproven that the better the control of blood glucose, the lesser thecomplications of diabetes. The main acute complication in type 1diabetes is hypoglycemia. This problem has been greatly enhanced byintroduction of tight glucose control. Because of the threat ofhypoglycemia, many patients will relax their glucose control in order tominimize the problem of hypoglycemia, which then increases the threat ofchronic complications. Thus, hypoglycemia is the limiting factor in thetreatment of type 1 diabetes. In addition, many non-diabetic subjectssuffer from episodes of hypoglycemia of unknown etiology. One of themain problems in diabetic subjects is defective counterregulation(mainly glucagon, epinephrine, norepinephrine, and cortisol responses)to hypoglycemia.

The initial abnormal counterregulatory response in diabetes (1) isdiminished glucagon responsiveness. This is paradoxical because theglucagon response to neurogenic stress (2;3) and exercise (4-7) isnormal. One explanation for the discrepancy between hypoglycemia andother stress responses is that the α-cell becomes more sensitive to theinhibitory effect of insulin in diabetes because in type 1 diabetes,most β-cells are destroyed. The sensitivity of α-cells duringhypoglycemia improves when normoglycemia is achieved by chronicphloridzin, but not by insulin treatment in diabetic rats (1). This isnot surprising because it is well known that insulin inhibits glucagonsynthesis and release (8). It is suggested that insulin released fromβ-cells acts directly on α-cells. It is known that α-cells have insulinreceptors. When insulin binds to those receptors, a cytosolic receptor(GABA_(A)R) is translocated to the cell membrane. This induces membranedepolarization and consequently, glucagon secretion is suppressed(9;10). When hypoglycemia is induced with insulin in clinicalinvestigations in non-diabetic subjects, glucagon secretion promptlyincreases and consequently, normal blood glucose is restored. Thisoccurs because low blood glucose by itself increases glucagon release,and this effect is stronger than the inhibitory action of insulin onα-cells. In contrast, in type 1 diabetic subjects, there are very few orno β-cells in the pancreas, and therefore α-cells become sensitized toinsulin. Under those conditions, the effect of an increased amount ofinsulin in the blood is much stronger than the effect of low bloodglucose. Therefore, in diabetic patients which are insulin treated,insulin's effect on the α-cell is much stronger than the effect of bloodglucose, and consequently, during hypoglycemia, the glucagon response iseither greatly decreased or absent.

One additional possibility for the increased α-cell sensitivity toinsulin is the augmented amount of somatostatin in the pancreas indiabetic animals (11;12) as well as in diabetic humans (13). Instreptozotocin (STZ)-diabetic rats, there is: (1) hyperplasia andhypertrophy of somatostatin-containing δ-cells in the pancreas (13), (2)increased expression of pancreatic prosomatostatin mRNA (14;15), (3)increased pancreatic somatostatin (1), (4) distribution ofsomatostatin-secreting δ-cells in the central portions of islets cells(16).

The present inventors were the first to suggest 17 years ago thatexcessive somatostatin may inhibit glucagon release during hypoglycemia(11). It is well documented that somatostatin inhibits stimulatedsecretion of pancreatic glucagon.

In STZ-diabetic rats, the expression of the gene for pro-glucagon andpro-somatostatin are both markedly increased (15). This increasedconcentration of somatostatin is observed in diabetic rats, both duringeuglycemia (i.e. normal blood glucose concentrations) and hypoglycemia(1). Concentration of somatostatin in plasma is also increased duringeuglycemia and hypoglycemia in diabetic rats (1). However, despiteincreased gene expression of proglucagon, plasma concentrations ofglucagon are not increased during hypoglycemia in diabetic rats,presumably in part due to the marked elevation of somatostatin levels.

Somatostatin receptors are ubiquitously expressed in most tissues of thebody. So far, 5 different subtypes of somatostatin receptors have beendiscovered. It is not desirable to inhibit all somatostatin receptors,which may cause unfavourable side effects. The localization ofparticular receptor subtypes on different tissues allows for specificreceptor antagonists to exert specific inhibitory effects. Forprotection against hypoglycemia, the most important is inhibition ofsomatostatin receptors related to counterregulatory hormone releasewhich are found in the pancreas, adrenal gland, and hypothalamus of thebrain. Somatostatin receptor type 2 (SSTR2) are found in these tissues.Within the pancreas, SSTR2 are found nearly exclusively onglucagon-secreting α-cells in rodents (16,17). In humans as well,somatostatin exerts its inhibitory effect on glucagon secretion viaSSTR2 found on α-cells (18,19). In the adrenal gland, SSTR2 have beenwidely identified in the adrenal medulla of animals and humans (20,21).It has been shown that somatostatin inhibits acetylcholine-stimulatedrelease of epinephrine from the adrenal medulla (22,23), and this is themechanism whereby epinephrine is released during hypoglycemia (24).SSTR2 are also found in the hypothalamus of the brain (25,26) wheresomatostatin also has an inhibitory effect on hormones involved inhypoglycemic counterregulation.

In isolated islets and in perifused isolated islets, the somatostatinreceptor type 2 (SSTR2)-selective antagonist, DC-41-33, also known asPRL2903 dose-dependently increases glucagon secretion to an argininestimulus, and subsequently adding somatostatin dose-dependently reversesthe actions of the SSTR2 antagonist (27;28). In isolated, perfusedpancreas of non-diabetic rats, this antagonist enhances glucagonsecretion without affecting insulin secretion (28). It is also able toreverse the inhibitory effect of glucose-dependent insulinotropicpolypeptides, GIP and GIP-(1-30)NH₂, and glucagon-like polypeptide,GLP-1(7-36)NH₂, on pentagastrin-stimulated gastric acid secretion innon-diabetic rats (29).

Previous experiments (28) showed the effect of the SSTR antagonist inisolated islets and pancreas (in vitro and ex vivo) but not in vivo. Theeffect of any SSTR antagonist has never been tested in diabetic animals.Since the glucagon response to a variety of stresses is normal indiabetic animals, including humans, and the defect is only noted duringinsulin-induced hypoglycemia in animals, including humans, it isessential to test the effect of any somatostatin, or somatostatinreceptor, antagonist in animal models of type 1 diabetes and in diabetichumans.

Somatostatin receptor antagonists are described in U.S. Pat. No.4,508,711 (April 1985, Coy et al.) and in U.S. Pat. No. 5,846,934(December 1998, Bass et al.). They showed that these antagonists canincrease the release of growth hormone, insulin, and glucagon. Theseantagonists were never tested in diabetic animals and humans, and it wasnot known whether these antagonists are effective during hypoglycemiawhen glucagon release is markedly decreased because of the enhancedsensitivity to β-cells to insulin.

Somatostatin also inhibits the secretions of corticotrophin-releasinghormone (CRH) and adrenocorticotrophic hormone (ACTH), and cortisol(i.e. hypothalamo-pituitary-adrenal (HPA) function) (30). Thus, it is ofclinical interest to investigate the effect of SSTR antagonists oncounterregulatory HPA hormone responses during hypoglycemia. Thequestion of whether SSTR antagonists can improve or normalize theresponse of glucocorticoids to hypoglycemia or other stresses has neverbeen investigated before. The present inventors have previously shownthat carbachol, an analog of acetylcholine, injected into the thirdventricle (icv) of dogs (a model of stress) increases the release ofcortisol (2). However, when somatostatin was infused icv concurrentlywith carbachol, the cortisol responses were abolished in bothnon-diabetic and diabetic dogs (2;31). Therefore, a SSTR antagonistcould enhance the release of cortisol also through a central mechanismand provide a mechanism whereby an SSTR2 antagonist also markedlyincreased the corticosterone response to hypoglycemia in diabetic rats.An additional possibility is an enhancement of corticosterone throughSSTRs in the adrenal cortex, although literature has yet to report SSTRin the corticosterone synthesizing fasciculata and reticularis zonae ofthe adrenal cortex (32-35).

Since the α-cell is excessively sensitive to insulin in diabetic animalsand humans, the key question is whether in an animal model of type 1diabetes a somatostatin or SSTR antagonist can increase glucagonrelease. Hypoglycemia is the main limiting factor of intensive insulintreatment. A pharmaceutical approach which could decrease the danger ofhypoglycemia would improve glycemic control in diabetic patients andcould thus diminish the risk of other complications of diabetes.

Most type 1 diabetic patients suffer from frequent episodes of low bloodglucose. This problem is exaggerated with tight control of blood glucoseinduced by frequent insulin administration. Tight control of bloodglucose is necessary to minimize the danger of life-threatening diabeticcomplications. The danger of hypoglycemia, however, limits thepossibility of desired tight control.

SUMMARY OF THE INVENTION

The present inventors have demonstrated that the response ofcounterregulatory hormones can be normalized in diabetic subjects byinhibiting the action of somatostatin, thereby reducing the threat ofhypoglycemia. In particular, the present inventors have shown thatsomatostatin receptor (SSTR) antagonists may be used to improve ornormalize the glucagon response to hypoglycemia in diabetic rats. Thepresent disclosure is directed at improving glucagon release when plasmaglucose levels are low due to excessive amounts of exogenous insulin.The present inventors have shown that with euglycemia, the inhibition ofsomatostatin does not alter plasma glucose levels, which is desirable.This is desirable because the original purpose of exogenous insulintreatment in type 1 diabetic patients is to maintain stringent controlof plasma glucose levels. Therefore, having an antagonist that wouldincrease plasma glucose levels during euglycemia would be undesirable.

Accordingly, the present disclosure provides the use of a somatostatininhibitor for controlling tight blood glucose levels in a subject inneed thereof. The present disclosure also provides the use of asomatostatin inhibitor for preparing a medicament for controlling tightblood glucose levels in a subject in need thereof. The presentdisclosure further provides a method for controlling tight blood glucoselevels comprising administering a somatostatin inhibitor to a subject inneed thereof.

In another embodiment, the present disclosure provides the use of asomatostatin inhibitor for treating or preventing hypoglycemia in asubject in need thereof. The present disclosure also provides the use ofa somatostatin inhibitor for preparing a medicament for treating orpreventing hypoglycemia in a subject in need thereof. Further, thepresent disclosure provides a method for treating or preventinghypoglycemia comprising administering a somatostatin inhibitor to asubject in need thereof.

In one embodiment, the subject is an insulin-dependent diabetic subject.In another embodiment, the subject suffers from idiopathic hypoglycemia.In a further embodiment, the subject has an insulinoma tumor.

Other features and advantages of the present invention will becomeapparent from the following detailed description. It should beunderstood, however, that the detailed description and the specificexamples while indicating preferred embodiments of the invention aregiven by way of illustration only, since various changes andmodifications within the spirit and scope of the invention will becomeapparent to those skilled in the art from this detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will now be described in relation to the drawings inwhich:

FIG. 1 indicates levels of plasma glucose levels in four groups of ratsduring the 1-h SSTR antagonist/saline pretreatment and 3-h hypoglycemicclamp experiment. FIG. 1A shows plasma glucose concentrations during thehypoglycemic clamp experiment using an insulin dose of 10 U/kg and SSTRantagonist dose of 1500 nmol/kg/h. A similar glycemic profile isobserved in FIG. 1B when another dose of insulin and SSTR antagonistwere tested (5 U/kg and 3000 nmol/kg/h, respectively).

FIG. 2 shows the effect of hypoglycemia induced with 10 U/kg insulininjection on plasma glucagon levels. SSTR antagonist dose was 1500nmol/kg/h.

FIG. 3 shows infusion of a smaller dose of insulin (5 U/kg). A largerdose of SSTR antagonist (3000 nmol/kg/h) was also used to see if theresponse in diabetic rats could be augmented.

FIG. 4 indicates the responses of corticosterone during hypoglycemiawhen insulin dose was 10 U/kg and SSTR antagonist was 1500 nmol/kg/h.Non-diabetic rats (N-ctrl) responded to hypoglycemia, but there was noresponse in diabetic rats (D-ctrl). With SSTR antagonist treatment,corticosterone response was augmented to the same extent in bothnon-diabetic 9N+SSTRa) and diabetic (D+SSTRa) rats.

FIG. 5 shows the corticosterone response to hypoglycemia when insulindose was 5 U/kg and SSTR antagonist was 3000 nmol/kg/h. Corticosteroneresponse was again lower in diabetic (D-ctrl) than in non-diabetic(N-ctrl) rats, but with SSTR antagonist, the corticosterone response wasfully normalized in diabetic rats (D+SSTRa).

FIG. 6 demonstrates the effect of somatostatin receptor type 2antagonism on glucose infusion requirement during 3 h of hypoglycemiawhen 5 U/kg insulin and 3000 nmol/kh/h SSTR antagonist were used.

FIG. 7 demonstrates that SSTR antagonist (1500 nmol/kg/h) given todiabetic rats dramatically increased (4-fold, AUC) plasma epinephrinelevels in response to hypoglycemia (insulin: 10 U/kg).

FIG. 8 indicates that there was no effect of the SSTR antagonist (1500nmol/kg/h) on plasma norepinephrine, neither during basal infusion ofSSTR antagonist nor during insulin-induced hypoglycemia (insulin: U/kg).

FIG. 9 shows that a growth hormone response to hypoglycemia (insulin: 5U/kg) was not observed in diabetic or non-diabetic rats.

DETAILED DESCRIPTION OF THE INVENTION

The inventors were the first to demonstrate that in diabetic rats, asomatostatin receptor type (SSTR) 2 antagonist can normalize responsesof glucagon and corticosterone in insulin-induced hypoglycemia. Aneffective glucagon response to hypoglycemia can rapidly increase glucoseproduction by the liver, and thus normoglycemia can be quickly restored.During prolonged episodes of hypoglycemia, glucocorticoids increaseglucose production by the liver and decrease glucose utilization in manytissues. Normalization of increases of both hormones is ideal forcontrol of blood glucose levels in diabetic patients. Thus, this novelpharmacological approach could have an effect on a number ofcounterregulatory hormones during hypoglycemia. The most importantcounterregulatory hormones are glucagon, epinephrine, cortisol (inhumans) or corticosterone (in rodents), norepinephrine, and, under someconditions, growth hormone. The primary purpose of this approachtherefore is to increase the response of these counterregulatoryhormones during insulin-induced hypoglycemia in diabetic patients asthese hormones will act to restore normal glucose levels. It is alsoimportant for safety reasons that the administration of an SSTRantagonist does not affect the basal levels of these counterregulatoryhormones in individuals (either diabetic or non-diabetic populations)not experiencing hypoglycemia. This is because increased basal levels ofcounterregulatory hormones would increase the amount of insulin neededto achieve optimal glucose control in insulin-treated diabetics. Thedata indicate that the antagonist does not substantially increase basalconcentration of these hormones.

Accordingly, the present disclosure provides the use of a somatostatininhibitor for controlling tight blood glucose levels in a subject inneed thereof. The present disclosure also provides the use of asomatostatin inhibitor for preparing a medicament for controlling tightblood glucose levels in a subject in need thereof. The presentdisclosure further provides a method for controlling tight blood glucoselevels comprising administering an effective amount of a somatostatininhibitor to a subject in need thereof.

The present disclosure also provides a method of treating or preventinghypoglycemia comprising administering an effective amount of asomatostatin inhibitor to a subject in need thereof. The presentdisclosure also provides the use of a somatostatin inhibitor fortreating or preventing hypoglycemia in a subject in need thereof. Thepresent disclosure also provides the use of a somatostatin inhibitor forpreparing a medicament for treating or preventing hypoglycemia in asubject in need thereof.

Hypoglycemia is a term understood in the art to mean a blood glucoselevel below normal. Normal fasting blood glucose levels fall within therange of 4.0 to 6.0 mM, and fed levels in non-diabetic individuals are≦7.0 mM. In one embodiment, a hypoglycemic blood glucose level isconsidered to be <4.0 mM. Hypoglycemic coma can occur below 2.0 mM. Inthe present experiments, the target range of hypoglycemia was 2.75±0.25mM.

The term “controlling tight blood glucose levels” means minimizing thetime that the blood glucose level is above or below the normal bloodglucose level of 4.0 to 6.0 mM in a subject.

The term “treating hypoglycemia” as used herein means improving orincreasing the glucagon response or improving or increasing thecorticosterone response. In one embodiment, treating hypoglycemia meansraising the blood glucose level back to normal glucose levels (i.e. 4.0to 6.0 mM). The term “preventing hypoglycemia” as used herein meansmaintaining a normal blood glucose level (i.e. 4.0 to 6.0 mM) wheninsulin is administered.

Hypoglycemia can be insulin-induced in a diabetic subject. Accordingly,in one embodiment, the subject is an insulin-dependent diabetic subject.In another embodiment, the diabetic subject suffers from type Idiabetes. In yet another embodiment, the diabetic subject suffers fromtype 11 diabetes.

Some non-diabetic individuals suffer from low blood glucose(hypoglycemia) of unknown origin. This is called idiopathichypoglycemia. These patients suffer from occasional hypoglycemia whichmay be prevented by use of chronic treatment with a somatostatininhibitor. The inhibitor increases the release of counterregulatoryhormones, which consequently increases glucose production by the liverand inhibits glucose uptake by peripheral tissues, thereby minimizing orpreventing such hypoglycemic episodes. Accordingly, in anotherembodiment, the subject suffers from idiopathic hypoglycemia.

Insulinoma is a malignant tumour of the pancreas that produces excessiveamounts of insulin. Therefore, blood glucose is low for most of thetime. Chronic treatment using a somatostatin inhibitor preventshypoglycemia in patients suffering from insulinoma. The patients do notrequire the inhibitor after the tumour has been removed. If the tumourcannot be removed, or if there are metastases, the inhibitor is used asan adjunct to other treatment modalities of the metastatic cancer.Accordingly, in a further embodiment, the subject has an insulinoma.

In one embodiment, the subject is an animal. The term “animal” includesall members of the animal kingdom, preferably a mammal, and morepreferably, a human.

A person skilled in the art would readily be able to determine if anindividual suffers from type 1 or type 2 diabetes. For example, anindividual's blood glucose levels can be measured in order to determineif they are diabetic. Diabetes is diagnosed if fasting plasma glucoseis >7.0 mM on 2 separate occasions. Normal fasting glucose is consideredbetween 4.0 and 6.0 mM, and impaired fasting glucose (“prediabetes”) isbetween 6.0 and 7.0 mM. Diabetes is also diagnosed if the 2 hour plasmaglucose is >11.1 mM after a 75 g oral glucose tolerance test. A randomglucose of >11.1 mM with symptoms of hyperglycemia on one occasion isalso considered diagnostic of diabetes. Type 1 diabetes can bedistinguished from type 2 diabetes using available criteria, such asthose of the American Diabetes Association (36). An insulin-dependentdiabetic as used herein means a diabetic subject whose blood glucose iscontrolled by insulin.

The predominant form of somatostatin released from pancreas, brain, andstomach is designated SST-14. SST-14 is a peptide having the amino acidsequence Ala-Gly-Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys (SEQ IDNO:1) and is cyclized by a disulfide bond between the cysteine residues.The predominant form of somatostatin in the intestines is designatedSST-28 and has an amino acid sequenceSer-Ala-Asn-Ser-Asn-Pro-Ala-Met-Ala-Pro-Arg-Glu-Arg-Lys-Ala-Gly-Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys(SEQ ID NO:2) and is cyclized by a disulfide bond between the cysteineresidues. The full human and rat pre-protein sequences are shown inTable 1, and the nucleic acid sequences are shown in Table 4.

There are 5 somatostatin receptors having a chromosomal localization andtissue distribution as shown in Table 2. The amino acid sequences of thehuman and rat somatostatin receptors are shown in Table 3 and thenucleic acid sequences are shown in Table 5.

A “somatostatin inhibitor” as used herein includes any substance that iscapable of inhibiting the expression or activity of somatostatin andthus, includes substances that inhibit somatostatin or the interactionof somatostatin with the somatostatin receptor. Such inhibitorsoptionally include antisense nucleic acid molecules, proteins,antibodies (and fragments thereof), small molecule inhibitors and othersubstances. In a preferred embodiment, the somatostatin inhibitor istargeted to the pancreas.

Accordingly, in one embodiment, the somatostatin inhibitor is anantisense nucleic acid of the somatostatin nucleic acid sequence shownin SEQ ID NO:15 or SEQ ID NO:16. In another embodiment, the somatostatininhibitor is an antisense nucleic acid of the somatostatin receptornucleic acid sequence shown in any one of SEQ ID NOs:17-26. In aparticular embodiment, the somatostatin inhibitor is an antisensenucleic acid of the somatostatin receptor 2 nucleic acid sequence asshown SEQ ID NO:19 or SEQ ID NO:20.

The term “antisense nucleic acid” as used herein means a nucleic acidthat is produced from a sequence that is inverted relative to its normalpresentation for transcription. Antisense nucleic acid molecules may bechemically synthesized using naturally occurring nucleotides orvariously modified nucleotides designed to increase the biologicalstability of the molecules or to increase the physical stability of theduplex formed with mRNA or the native gene e.g. phosphorothioatederivatives and acridine substituted nucleotides. The antisensesequences may be produced biologically using an expression vectorintroduced into cells in the form of a recombinant plasmid, phagemid orattenuated virus in which antisense sequences are produced under thecontrol of a high efficiency regulatory region, the activity of whichmay be determined by the cell type into which the vector is introduced.

In one embodiment, the somatostatin inhibitor is an antibody that bindsto the somatostatin protein having the amino acid sequence as shown inany one of SEQ ID NOs:1-4. In another embodiment, the somatostatininhibitor is an antibody that binds to the somatostatin receptor havingthe amino acid sequence as shown in any one of SEQ ID NOs: 5-14. In aparticular embodiment, the antibody is specific to the somatostatinreceptor 2 having the amino acid sequence as shown in SEQ ID NO:7 or SEQID NO:8.

The term “antibody” as used herein is intended to include fragmentsthereof which also specifically react with a somatostatin or asomatostatin receptor. Antibodies can be fragmented using conventionaltechniques and the fragments screened for utility in the same manner asdescribed below. For example, F(ab′)₂ fragments can be generated bytreating antibody with pepsin. The resulting F(ab′)₂ fragment can betreated to reduce disulfide bridges to produce Fab′ fragments.

Conventional methods can be used to prepare antibodies. For example, byusing a somatostatin or peptide from a somatostatin receptor, polyclonalantisera or monoclonal antibodies can be made using standard methods. Amammal, (e.g., a mouse, hamster, or rabbit) can be immunized with animmunogenic form of the peptide which elicits an antibody response inthe mammal. Techniques for conferring immunogenicity on a peptideinclude conjugation to carriers or other techniques well known in theart. For example, the peptide can be administered in the presence ofadjuvant. The progress of immunization can be monitored by detection ofantibody titers in plasma or serum. Standard ELISA or other immunoassayprocedures can be used with the immunogen as antigen to assess thelevels of antibodies. Following immunization, antisera can be obtainedand, if desired, polyclonal antibodies isolated from the sera.

To produce monoclonal antibodies, antibody producing cells (lymphocytes)can be harvested from an immunized animal and fused with myeloma cellsby standard somatic cell fusion procedures thus immortalizing thesecells and yielding hybridoma cells. Such techniques are well known inthe art, (e.g., the hybridoma technique originally developed by Kohlerand Milstein (37) as well as other techniques such as the human B-cellhybridoma technique (38), the EBV-hybridoma technique to produce humanmonoclonal antibodies (39) and screening of combinatorial antibodylibraries (40). Hybridoma cells can be screened immunochemically forproduction of antibodies specifically reactive with the peptide and themonoclonal antibodies can be isolated. Therefore, the invention alsocontemplates hybridoma cells secreting monoclonal antibodies withspecificity for a somatostatin or somatostatin receptor.

Chimeric antibody derivatives, i.e., antibody molecules that combine anon-human animal variable region and a human constant region are alsocontemplated within the scope of the invention. Chimeric antibodymolecules can include, for example, the antigen binding domain from anantibody of a mouse, rat, or other species, with human constant regions.Conventional methods may be used to make chimeric antibodies containingthe immunoglobulin variable region which recognizes a somatostatin orsomatostatin receptor protein (See, for example, Morrison et al. (41),and Takeda et al. (42), and the patents of Cabilly et al., U.S. Pat. No.4,816,567; Boss et al., U.S. Pat. No. 4,816,397; Tanaguchi et al.,European Patent Publication EP171496; European Patent Publication0173494, United Kingdom patent GB 2177096B).

Monoclonal or chimeric antibodies specifically reactive with asomatostatin or somatostatin receptor as described herein can be furtherhumanized by producing human constant region chimeras, in which parts ofthe variable regions, particularly the conserved framework regions ofthe antigen-binding domain, are of human origin and only thehypervariable regions are of non-human origin. Such immunoglobulinmolecules may be made by techniques known in the art, (e.g., Teng et al.(43), Kozbor et al. (38); Olsson et al. (44) and PCT PublicationWO92/06193 or EP 0239400). Humanized antibodies can also be commerciallyproduced (Scotgen Limited, 2 Holly Road, Twickenham, Middlesex, GreatBritain).

Specific antibodies, or antibody fragments, reactive against asomatostatin or somatostatin receptor may also be generated by screeningexpression libraries encoding immunoglobulin genes, or portions thereof,expressed in bacteria with peptides produced from the nucleic acidmolecules encoding a somatostatin or somatostatin receptor. For example,complete Fab fragments, VH regions and FV regions can be expressed inbacteria using phage expression libraries (See for example Ward et al.(45), Huse et al. (40) and McCafferty et al (46)).

Antibodies may also be prepared using DNA immunization. For example, anexpression vector containing a nucleic acid encoding a somatostatin orsomatostatin receptor may be injected into a suitable animal such asmouse. The protein will therefore be expressed in vivo and antibodieswill be induced. The antibodies can be isolated and prepared asdescribed above for protein immunization.

The somatostatin inhibitors include SSTR antagonists. The term“antagonist” as used herein means any molecule that is capable ofblocking or decreasing the amount of ligand binding to the receptor, ora molecule that binds to the ligand such that signaling through thereceptor is diminished or abolished. “SSTR antagonist” as used hereinmeans an antagonist of a somatostatin receptor, including SSTR2. “SSTR2antagonist” as used herein is an SSTR antagonist that has a higheraffinity or selectivity for SSTR2 compared to other types of SSTRs.

Accordingly, in an embodiment, the somatostatin inhibitor is an SSTRantagonist. In one embodiment, the somatostatin inhibitor is a SSTR2antagonist. In another embodiment, the SSTR2 antagonist is a peptide.Peptide antagonists of SSTR2 are known in the art and have beendescribed widely in the literature (47-49) (all of which are hereinincorporated in their entirety by reference) and in a number of patentsand patent applications that claim binding with one or more somatostatinsubtype receptors including SSTR2. These include but are not limited tothe novel cyclic peptide antagonists disclosed in U.S. Pat. No.4,508,711; U.S. Pat. No. 4,505,897; PCT application WO02072602; USApplication No. 24181032A1; US Application No. 28020970A1; and PCTapplication WO02072602 by Coy et al. (all of which are hereinincorporated in their entirety by reference). In addition, Morgan,Murphy and Coy also disclose other somatostatin receptor antagonistsbased on a variable octapeptide structures in PCT Application WO09824807(incorporated in its entirety by reference). Similarly, Bass et al havedisclosed other novel cyclic peptides that are SSTR2 antagonists in U.S.Pat. No. 5,846,934 and Baumbach et al have also disclosed a number ofdifferent structures that include cyclic peptides in U.S. Pat. No.5,925,618 (both of which are incorporated herein in their entirety byreference). A listing of some disclosed SSTR antagonists is given inTable 6 and a subset of these antagonists is provided in Table 7.

Accordingly, in one embodiment, the somatostatin inhibitor is an SSTRantagonist having a peptide sequence as shown in SEQ ID NOs: 27-436 (seeTable 6). In another embodiment, the somatostatin inhibitor is an SSTRantagonist having a peptide sequence as shown in SEQ ID NOs:27-120. Inanother embodiment, the somatostatin inhibitor is an SSTR antagonisthaving a peptide sequence as shown in SEQ ID NOs. 27-34 (Table 7). Inyet a further embodiment, the SSTR antagonist is a cyclic-octapeptide asshown in SEQ ID NO:28: H-Fpa-cyclo[DCys-Pal-DTrp-Lys-Tle-Cys]-Nal-NH2also known as DC-14-33. Each embodiment includes an equivalentpharmaceutical salt thereof.

In another embodiment, the somatostatin inhibitor is a SSTR2 antagonistbased on small molecule organic structures. In particular, Hay et alhave disclosed a number of different somatostatin antagonists andagonists that act at the SST subtype 2 receptor in the followingpatents: U.S. Pat. No. 6,495,589; U.S. Pat. No. 6,696,418; U.S. Pat. No.6,720,330 and related applications: US21047030A1, US22016289A1,US22091090A1, US22091125A1, US22128206A1, US24157834A1 and US25054581A1(all of which are herein incorporated in their entirety by reference).Similarly, Carpino et al disclose a number of chemical structures thatalso target the SST subtype 2 receptor in U.S. Pat. No. 6,867,202 andUS23100561A1 (both of which are herein incorporated in their entirety byreference). As well, Thurieau et al disclose a number of imidazolylderivatives in US20040176379A1 and Troxler also discloses a number ofnovel non-peptide samatostatin antagonists in U.S. Pat. No. 6,635,647and U.S. Pat. No. 6,861,430 (all of which are herein incorporated intheir entirety by reference).

The somatostatin inhibitors may also contain or be used to obtain ordesign “peptide mimetics”. For example, a peptide mimetic may be made tomimic the function of an SSTR antagonist. “Peptide mimetics” arestructures which serve as substitutes for peptides in interactionsbetween molecules (See Morgan et al (1989), Ann. Reports Med. Chem.24:243-252 for a review). Peptide mimetics include synthetic structureswhich may or may not contain amino acids and/or peptide bonds but retainthe structural and functional features protein of the invention,including biological activity and a reduced propensity to activate humanT cells. Peptide mimetics also include peptoids, oligopeptoids (Simon etal (50)).

Peptide mimetics may be designed based on information obtained bysystematic replacement of L-amino acids by D-amino acids, replacement ofside chains with groups having different electronic properties, and bysystematic replacement of peptide bonds with amide bond replacements.Local conformational constraints can also be introduced to determineconformational requirements for activity of a candidate peptide mimetic.The mimetics may include isosteric amide bonds, or D-amino acids tostabilize or promote reverse turn conformations and to help stabilizethe molecule. Cyclic amino acid analogues may be used to constrain aminoacid residues to particular conformational states. The mimetics can alsoinclude mimics of the secondary structures of the proteins of theinvention. These structures can model the 3-dimensional orientation ofamino acid residues into the known secondary conformations of proteins.Peptoids may also be used which are oligomers of N-substituted aminoacids and can be used as motifs for the generation of chemically diverselibraries of novel molecules.

The methods described include giving the antagonist to a subject at anyblood glucose level. Accordingly in one embodiment, the subject has anyblood glucose level. In another embodiment, the subject has a bloodglucose level of less than 4.0 mM.

The purpose of using a somatostatin inhibitor is to prevent the patientfrom becoming hypoglycemic. When the subject is already hypoglycemic,glucose or glucagon could be given as well. The goal of treatment with asomatostatin inhibitor in an insulin-dependent diabetic subject beforeinsulin injection is to prevent a hypoglycemic episode. Accordingly, ina further embodiment, the invention provides a treatment regimen forcontrolling blood glucose comprising:

(a) monitoring the blood glucose level in a diabetic subject;

(b) administering a somatostatin inhibitor to the diabetic subjectbefore insulin injection when blood glucose levels are normal or belownormal, i.e. when the blood glucose level in (a) is in the range of 4.0to 6.0 mM or less than 4.0 mM, and

(c) administering insulin to the diabetic subject when the blood glucoselevel in (a) is in the range of 5.0 to 15.0 mM;

(d) repeating steps (a) and (b) to control the blood glucose levelwherein controlling the blood glucose level means that the blood glucoselevel is in the range of 4.0 to 6.0 mM.

The disclosure also provides a pharmaceutical composition forcontrolling tight blood glucose levels in a subject in need thereofcomprising a somatostatin inhibitor and a pharmaceutically acceptablecarrier, diluent or excipient.

The disclosure further provides a pharmaceutical composition fortreating or preventing hypoglycemia in a subject comprising asomatostatin inhibitor and a pharmaceutically acceptable carrier,diluent or excipient.

In one embodiment, the subject is an insulin-dependent diabetic subject.In another embodiment, the subject suffers from idiopathic hypoglycemia.In a further embodiment, the subject has an insulinoma.

The somatostatin inhibitors may be formulated into pharmaceuticalcompositions for administration to subjects in a biologically compatibleform suitable for administration in vivo. By “biologically compatibleform suitable for administration in vivo” is meant a form of thesubstance to be administered in which any toxic effects are outweighedby the therapeutic effects. The substances may be administered to livingorganisms including humans, and animals. Administration of atherapeutically active or effective amount of the pharmaceuticalcompositions of the present invention is defined as an amount effective,at dosages and for periods of time necessary to achieve the desiredresult. For example, a therapeutically active or effective amount of asubstance may vary according to factors such as the disease state, age,sex, and weight of the individual, and the ability of protein to elicita desired response in the individual. Dosage regime may be adjusted toprovide the optimum therapeutic response. For example, several divideddoses may be administered daily or the dose may be proportionallyreduced as indicated by the exigencies of the therapeutic situation.

The active substance may be administered in a convenient manner such asby injection (subcutaneous, intravenous, intramuscular, etc.), oraladministration, inhalation, transdermal administration (such as topicalcream or ointment, etc.), or suppository applications. Depending on theroute of administration, the active substance may be coated in amaterial to protect the compound from the action of enzymes, acids andother natural conditions which may inactivate the compound. The activesubstance may be formulated into delayed release formulations such thatblood glucose levels can be controlled or hypoglycemia prevented forlonger periods of time than a conventional formulation.

The compositions described herein can be prepared by per se knownmethods for the preparation of pharmaceutically acceptable compositionswhich can be administered to subjects, such that an effective quantityof the active substance is combined in a mixture with a pharmaceuticallyacceptable vehicle. Suitable vehicles are described, for example, inRemington's Pharmaceutical Sciences (Remington's Pharmaceutical Sciences(2000—20th edition) Mack Publishing Company). On this basis, thecompositions include, albeit not exclusively, solutions of thesubstances in association with one or more pharmaceutically acceptablevehicles or diluents, and contained in buffered solutions with asuitable pH and iso-osmotic with the physiological fluids.

The above disclosure generally describes the present invention. A morecomplete understanding can be obtained by reference to the followingspecific examples. These examples are described solely for the purposeof illustration and are not intended to limit the scope of theinvention. Changes in form and substitution of equivalents arecontemplated as circumstances might suggest or render expedient.Although specific terms have been employed herein, such terms areintended in a descriptive sense and not for purposes of limitation.

The following non-limiting examples are illustrative of the presentinvention:

EXAMPLES Results

Non-diabetic and STZ-diabetic rats were injected with insulin (10 U/kgand 5 U/kg). These doses yielded reproducible responses of plasmaglucose (FIG. 1). In diabetic rats, plasma glucose is elevatedapproximately 3- to 4-fold before hypoglycemia is induced. Asubcutaneous injection of insulin was given immediately after the samplewas taken at time 0 in all groups of rats to induce hypoglycemia. Plasmaglucose levels dropped to the same target hypoglycemia (2.75±0.25 mM) inboth non-diabetic and diabetic rats. The plasma glucose levels arecomparable in all 4 groups because whenever necessary, a small amount ofglucose would be infused intravenously to maintain plasma glucose levelsin the target range. This technique of glucose clamping is awell-established method in diabetes research which allows precisecomparison between different groups at a specific glycemic level.

It can be seen that while non-diabetic rats (N-ctrl) have a robustglucagon response to low plasma glucose levels, diabetic control rats(D-ctrl) did not respond at all. When SSTR antagonist was infused beforeand after insulin injection, the glucagon response was markedlyaugmented in non-diabetic rats (N+SSTRa). With the high insulin dose innon-diabetic rats, insulin induced a 3-fold greater increase in plasmaglucagon when the SSTR2 antagonist was given (1500 nmol/kg/h) (FIG. 2).In diabetic rats (D+SSTRa), glucagon was increased during SSTR2antagonist infusion before insulin was given, and this increase inplasma glucagon was maintained throughout hypoglycemia (FIG. 2), andyielded a more modest increase in plasma glucagon.

Subsequently, a lower dose of insulin (5 U/kg) was used, which is moresimilar to the clinical situation, and a higher dose of the antagonist(3000 nmol/kg/h) to find out whether under those conditions, theantagonist would be more efficient in increasing the glucagon responseto hypoglycemia. In non-diabetic rats (N-ctrl), a robust glucagonhypoglycemia is seen. In contrast, the response of diabetic rats(D-ctrl) was greatly decreased as compared to their non-diabeticcounterparts (FIG. 3). With the SSTR2 antagonist, the peak glucagonresponse of diabetic rats (D+SSTRa) was almost 7-fold increased indiabetic rats (FIG. 3) and there was a tendency to even exceed that ofnon-diabetic controls. This is also shown by calculating the area underthe curve (AUC) in the same figure. The enhancement of the glucagonresponse in diabetic rats infused with SSTR2 antagonist is highlysignificant (P<0.03).

The SSTR2 antagonist infusion fully normalized the defectivecorticosterone response to hypoglycemia in diabetic rats (FIG. 5). Thisrestoration of the corticosterone response was highly significant(P<0.03). There were also increases in the corticosterone response tohypoglycemia in both SSTR2 antagonist-treated non-diabetic and diabeticrats even at the higher insulin dose and lower SSTR2 antagonist dose(FIG. 4).

To achieve comparable hypoglycemia in non-diabetic and diabetic ratsafter insulin is administered, it is necessary to clamp plasma glucoseconcentrations at a desired target level. This technique is referred toas the “glucose clamp” and is achieved by intravenously infusing glucosewhenever necessary.

A normal response to hypoglycemia is an increase of glucose productionby the liver due to the action of counterregulatory hormones (primarilyglucagon and epinephrine; corticosterone during prolonged hypoglycemia).Because of faulty counterregulatory hormone responses, diabetic rats canrespond to hypoglycemia with only attenuated glucose production.Therefore, it is anticipated that if the somatostatin SSTR2 antagonistcan improve counterregulatory hormone responses to hypoglycemia,endogenous glucose production in those animals should be increasedmarkedly. Consequently, less glucose infusion should be required duringhypoglycemia in animals which receive SSTR2 antagonist.

FIG. 6 clearly demonstrates that SSTR antagonist treatment results in alesser requirement of exogenous glucose administration in diabetic rats(D+SSTRa) compared with their untreated counterrparts (D-ctrl), i.e.less glucose infusion was necessary in both non-diabetic and diabeticrats receiving the SSTR2 antagonist than in controls that did notreceive the SSTR2 antagonist during the hypoglycemic clamp. Thissuggests that SSTR antagonist treatment may also increase production ofglucose during hypoglycemia in diabetic rats (D+SSTRa). The same patternof improvement is also observed in non-diabetic rats treated with theantagonist (N+SSTRa) compared to controls (N-ctrl). Requirements ofglucose infusion cannot be compared between non-diabetic and diabeticrats since the latter are insulin resistant. This marked variability ininsulin sensitivity is also observed in poorly controlled type 1diabetic patients. Because of faulty counterregulatory hormoneresponses, diabetic rats respond to hypoglycemia with attenuated glucoseproduction.

If the SSTR antagonist improves hormone counterregulation tohypoglycemia, endogenous glucose production is markedly increased.Consequently, less glucose infusion is required during hypoglycemia inanimals receiving SSTR antagonist.

SSTR antagonist (1500 nmol/kg/h) given to diabetic rats dramaticallyincreased (4-fold, AUC) plasma epinephrine levels in response tohypoglycemia (insulin: 10 U/kg) (FIG. 7). This marked activation ofepinephrine counterregulation was specific to hypoglycemia since basalinfusion of the SSTR antagonist did not affect plasma epinephrinelevels.

There was no effect of the SSTR antagonist (1500 nmol/kg/h) on plasmanorepinephrine, neither during basal infusion of SSTR antagonist norduring insulin-induced hypoglycemia (insulin: 10 U/kg) (FIG. 8). Takentogether, FIGS. 7 and 8 show that infusion of SSTR antagonist itselfdoes not stimulate an increase in circulating catecholamine levels,which indicates that SSTR antagonist administration, per se, does notelicit a stress hormone response.

A growth hormone response to hypoglycemia (insulin: 5 U/kg) was notobserved in diabetic or non-diabetic rats (FIG. 9). This may be becausethe peak growth hormone response was missed or because the hypoglycemiawas not prolonged sufficiently. SSTR antagonist (3000 nmol/kg/h) did notaffect GH levels in diabetic rats, regardless of hypoglycemia.

While the present invention has been described with reference to whatare presently considered to be the preferred examples, it is to beunderstood that the invention is not limited to the disclosed examples.To the contrary, the invention is intended to cover variousmodifications and equivalent arrangements included within the spirit andscope of the appended claims.

All publications, patents and patent applications are hereinincorporated by reference in their entirety to the same extent as ifeach individual publication, patent or patent application wasspecifically and individually indicated to be incorporated by referencein its entirety.

TABLE 1 Human Somatostatin Pre-Proprotein (NCBI: NP_001039 (SEQ IDNO:3))  1 mlscrlqcal aalsivlalg cvtgapsdpr lrqflqksla aaagkqelakyflaellsep 61 nqtendalep edlsqaaeqd emrlelqrsa nsnpamapre rkagcknffwktftsc Rat Somatostatin Pre-Proprotein (NCBI: NP_036791 (SEQ ID NO: 4)) 1 mlscrlqcal aalcivlalg gvtgapsdpr lrqflqksla aatgkqelak yflaellsep 61nqtendalep edlpqaaeqd emrlelqrsa nsnpamapre rkagcknffw ktftsc

TABLE 2 SST receptor type: SSTR1 SSTR2 SSTR3 SSTR4 SSTR5 Chromosomal14q13 17q24 22q13.1 20p11.2 16p13.3 localization: Tissue brain brainbrain brain brain distribution: pituitary pituitary pituitary isletpituitary islet islet (α- islet stomach islet (β- stomach cell) stomachlung cell) kidney stomach placenta stomach liver kidney Table adaptedfrom Patel, Y C. “Somatostatin and its receptor family.” Frontiers inNeuroendocrinology, 20: 157-198, 1999.

TABLE 3 Human Somatostatin Receptor Type 1 ((NCBI: NP_001040 (SEQ IDNO:5))   1 mfpngtassp ssspspspgs cgegggsrgp gagaadgmee pgrnasqngtlsegqgsail  61 isfiysvvcl vglcgnsmvi yvilryakmk tatniyilnl aiadellmlsvpflvtstll 121 rhwpfgallc rlvlavdavn mftsiycltv lsvdryvavv hpikaaryrrptvakvvnlg 181 vwvlsllvil pivvfsrtaa nsdgtvacnm lmpepaqrwl vgfvlytflmgfllpvgaic 241 lcyvliiakm rmvalkagwq qrkrserkit lmvmmvvmvf vicwmpfyvvqlvnvfaeqd 301 datvsqlsvi lgyanscanp ilygflsdnf krsfqrilcl swmdnaaeepvdyyatalks 361 raysvedfqp enleaggvfr ngtctsritt l Rat SomatostatinReceptor Type 1 (NCBI: NP_036851 (SEQ ID NO:6))   1 mfpngtapsptsspssspgg cgegvcsrgp gagaadgmee pgrnaaqngt leegqgsail  61 isfiysvvclvglcgnsmvi yvilryakmk tatniyilnl aiadellmls vpflvtstll 121 rhwpfgallcrlvlsvdavn mftsiycltv lsvdryvavv hpikaaryrr ptvakvvnlg 181 vwvlsllvilpivvfsrtaa nsdgtvacnm lmpepaqrwl vgfvlytflm gfllpvgaic 241 lcyvliiakmrmvalkagwq qrkrserkit lmvmmvvmvf vicwmpfyvv qlvnvfaeqd 301 datvsqlsvilgyanscanp ilygflsdnf krsfqrilcl swmdnaaeep vdyyatalks 361 raysvedfqpenlesggvfr ngtcasrist l Human Somatostatin Receptor Type 2 (NCBI:NP_001041 (SEQ ID NO:7)) On chromosome 17q24   1 mdmadeplng shtwlsipfdlngsvvstnt snqtepyydl tsnavltfiy fvvciiglcg  61 ntlviyvilr yakmktitniyilnlaiade lfmlglpfla mqvalvhwpf qkaicrvvmt 121 vdginqftsi fcltvmsidrylavvhpiks akwrrprtak mitmavwgvs llvilpimiy 181 aglrsnqwgr ssctinwpgesgawytgfii ytfilgflvp ltiiclcylf iiikvkssgi 241 rvgsskrkks ekkvtrmvsivvavfifcwl pfyifnvssv smaisptpal kgmfdfvvvl 301 tyanscanpi lyaflsdnfkksfqnvlclv kvsgtddger sdskqdksrl nettetqrtl 361 lngdlqtsi RatSomatostatin Receptor Type 2 (NCBI: NP_062221 (SEQ ID NO:8))   1meltseqfng sqvwipspfd lngslgpsng snqtepyydm tsnavltfiy fvvcvvglcg  61ntlviyvilr yakmktitni yilnlaiade lfmlglpfla mqvalvhwpf gkaicrvvmt 121vdginqftsi fcltvmsidr ylavvhpiks akwrrprtak minvavwgvs llvilpimiy 181aglrsnqwgr ssctinwpge sgawytgfii yafilgflvp ltiiclcylf iiikvkssgi 241rvgsskrkks ekkvtrmvsi vvavfifcwl pfyifnvssv svaisptpal kgmfdfvvil 301tyanscanpi lyaflsdnfk ksfqnvlclv kvsgaedger sdskqdksrl nettetqrtl 361lngdlqtsi Human Somatostatin Receptor Type 3 (NCBI: NP_001042 (SEQ IDNO:9))   1 mdmlhpssvs ttsepenass awppdatlgn vsagpspagl avsgvliplvylvvcvvgll  61 gnslviyvvl rhtaspsvtn vyilnlalad elfmlglpfl aaqnalsywpfgslmcrlvm 121 avdginqfts ifcltvmsvd rylavvhptr sarwrtapva rtvsaavwvasavvvlpvvv 181 fsgvprgmst chmqwpepaa awragfiiyt aalgffgpll viclcyllivvkvrsagrrv 241 wapscqrrrr serrvtrmvv avvalfvlcw mpfyvlnivn vvcplpeepaffglyflvva 301 lpyanscanp ilygflsyrf kqgfrrvllr parrvrsqep tvgppekteeedeeeedgee 361 sreggkgkem ngrvsqitqp gtsgqerpps rvaskeqqll pqeastgeksstmrisyl Rat Somatostatin Receptor Type 3 (NCBI: NP_598206 (SEQ IDNO:10))   1 maavtypssv pttldpgnas sawpldtslg nasagtslag lavagilislvylvvcvvgl  61 lgnslviyvv lrhtsspsvt svyilnlala dalfmlglpf laaqnalsywpfgslmcrlv 121 mavdginqft sifcltvmsv drylavvhpt rsarwrtapv armvsaavwvasavvvlpvv 181 vfsgvprgms tchmqwpepa aawrtafiiy taalgffgpl lviclcyllivvkvrsttrr 241 vrapscqwvq apacqrrrrs errvtrmvva vvalfvlcwm pfyllnivnvvcplpeepaf 301 fglyflvval pyanscanpi lygflsyrfk qgfrrillrp srrvrsqepgsgppekteee 361 edeeeeerre eeerrmqrgq emngrlsqia qpgpsgqqqr pctgtakeqqllpqeatagd 421 kastlshl Human Somatostatin Receptor Type 4 (NCBI:NP_001043 (SEQ ID NO:11))   1 msapstlppg geeglgtawp saanassapaeaeeavagpg daraagmvai qciyalvclv  61 glvgnalvif vilryakmkt attiyllnlavadelfmlsv pfvassaalr hwpfgsvlcr 121 avlsvdglnm ftsvfcltvl svdryvavvhplraatyrrp svaklinlgv wlasllvtlp 181 iaifadtrpa rgggavacnl qwphpawsavfvvytfllgf llpvlaiglc yllivgkmra 241 valragwqqr rrsekkitrl vlmvvvvfvlcwmpfyvvql lnlvvtslda tvnhvslils 301 yanscanpil ygflsdnfrr sfqrvlclrccllegaggae eepldyyata lkskggagcm 361 cpplkcqqea lqpepgrkri pltrtttf RatSomatostatin Receptor Type 4 (NCBI: NP_037168 (SEQ ID NO:12))   1mntpatlplg gedttwtpgi naswapdeee davrsdgtgt agmvtiqciy alvclvglvg  61nalvifvilr yakmktatni yllnlavade lfmlsvpfva saaalrhwpf gavlcravls 121vdglnmftsv fcltvlsvdr yvavvhplra atyrrpsvak linlgvwlas llvtlpiavf 181adtrpargge avacnlhwph pawsavfviy tfllgfllpv laigicylli vgkmravalr 241agwqqrrrse kkitrlvlmv vtvfvlcwmp fyvvqllnlf vtsldatvnh vslilsyans 301canpilygfl sdnfrrsfqr vlclrcclle ttggaeeepl dyyatalkar ggpgcicppl 361pcqqepmqae packrvpftk tttf Human Somatostatin Receptor Type 5 (NCBI:NP_001044 (SEQ ID NO:13))   1 meplfpastp awnasspgaa sgggdnrtlvgpapsagara vlvpvlyllv caaglggntl  61 viyvvlrfak mktvtniyil nlavadvlymlglpflatqn aasfwpfgpv lcrlvmtldg 121 vnqftsvfcl tvmsvdryla vvhplsaarwrrprvaklas aaawvlslcm slpllvfadv 181 qeggtcnasw pepvglwgav fiiytavlgffapllviclc yllivvkvra agvrvgcvrr 241 rserkvtrmv lvvvlvfagc wlpfftvnivnlavalpqep aaaglyffvv ilsyanscan 301 pvlygflsdn frqsfqkvlc lrkgsgakdadateprpdri rqqqeatppa hraaanglmq 361 tskl Rat Somatostatin Receptor Type5 (NCBI: NP_037014 (SEQ ID NO:14))   1 meplslastp swnasaassg nhnwslvgsaspmgaravlv pvlyllvctv glsgntlviy  61 vvlrhakmkt vtnvyilnla vadvlfmlglpflatqnavv sywpfgsflc rlvmtldgin 121 qftsifclmv msvdrylavv hplrsarwrrprvakmasaa vwvfsllmsl pllvfadvqe 181 gwgtcnlswp epvglwgaaf itytsvlgffgpllviclcy llivvkvkaa gmrvgssrrr 241 rsepkvtrmv vvvvlvfvgc wlpffivnivnlaftlpeep tsaglyffvv vlsyanscan 301 pllygflsdn frqsfrkvlc lrrgygmedadaieprpdks grpqatlptr sceanglmqt 361 sri

TABLE 4 Human Somatostatin Pre-Proprotein mRNA (NCBI: NM_001048 (SEQ IDNO:15))   1 gggagacggt tgagagcaca caagccgctt taggagcgag gttcggagccatcgctgctg  61 cctgctgatc cgcgcctaga gtttgaccag ccactctcca gctcggctttcgcggcgccg 121 agatgctgtc ctgccgcctc cagtgcgcgc tggctgcgct gtccatcgtcctggccctgg 181 gctgtgtcac cggcgctcac tcggacccca gactccgtaa gtttctgcagaagtccctgg 241 ctgctgccgc ggggaagcag gaactggcca agtacttctt ggcagagctgctgtctgaac 301 ccaaccagac ggagaatgat gccctggaac atgaagatct gtcccaggctgctgagcagg 361 atgaaatgag gcttgagctg cagagatctg ctaactcaaa accggctatggcacccagag 421 aacgcaaagc tggctgcaag aatttcttct ggaagacttt aacatcctgttagctttctt 481 aactagtatt gtccatatca gacctctgat ccctcgcccc caaaccccatctctcttccc 541 taatcctcca agtcttcagc gagacccttg cattagaaac tgaaaactgtaaatacaaaa 601 taaaattatg gtgaaattat gaaaaatgtg aaaaaaaaaa aaaaaaaaaaaaaaaaaaaa 661 aaaaa Rat Somatostatin Pre-Proprotein mRNA (NCBI:NM_012659 (SEQ ID NO:16))   1 tgcggacctg cgtctagact gacccacagcgctcaagctc ggctgtctga ggcaggggag  61 atgctgtcct gccgtctcca gtgcgcgctggccgcgctct gcatcgtcct ggctttgggc 121 ggtgtcaccg gggcgccctc ggaccccagactccgtcagt ttctgaagaa gtctctggcg 181 gctgccaccg ggaaacagga actggccaagtacttcttgg cagaactgct gtctgagccc 241 aaccagacag agaacgatgc cctggagcctgaggatttgc cccaggcagc tgagcaggac 301 gagatgaggc tggagctgca gaggtctgcaaactcgaacc cagccatggc accccgggaa 361 cgcaaagctg gctgcaagaa cttcttctggaagacattca catcctgtta gctttaatat 421 tgttgtctca gccagacctc tgatccctctcctccaaatc ccatatctat tccttaactc 481 ccagcccccc ccccaatgct caactagaccctgcgttaga aattgaagac tgtaaataca 541 aaataaaatt atggtgaaat tatg

TABLE 5 Human Somatostatin Receptor Type 1 mRNA (NCBI: NM_001049 (SEQ IDNO:17))    1 tggtcatcga acggaggcag ctcctcacat ggatttagaa gagctggcgtccccgcccgc   61 ccaagccttt aaactctcgt ctgccagaac ccgccaactc tccaggcttagggccagttt  121 cagagattat aagagtaatt gcgtgggcac ctgtgctggg gccaggcgcaaagaagggag  181 ttggtctgcg cgaagatcgt caacctgata acagaccgca catgcactttgcaccgacca  241 tctacgtctc agtatggagg ttgcgcactt tggctgctga cgcgctggtggtgcctatta  301 atcatttacc agtccagagc cgcgccagtt aatggctgtg ccgtgcggtgctaccacatc  361 ctggcctctc ctctccacgg tcgcctgtgc ccgggcaccc cggagctgcaaactgcagag  421 cccaggcaac cgctgggctg tgcgccccgc cggcgccggt aggagccgagatccccgcag  481 cggttgcgct atacccggag gcgctgggcg gctgtgggct gcaggcaagcggtcgggtgg  541 ggagggaggg cgcaggcggc gggtgcgcga ggagaaagcc ccagccctggcagccccact  601 ggcccccctc agctgggatg ttccccaatg gcaccgcctc ctctccttcctcctctccta  661 gccccagccc gggcagctgc ggcgaaggcg gcggcagcag gggccccggggccggcgctg  721 cggacggcat ggaggagcca gggcgaaatg cgtcccagaa cgggaccttgagcgagggcc  781 agggcagcgc catcctgatc tctttcatct actccgtggt gtgcctggtggggctgtgtg  841 ggaactctat ggtcatctac gtgatcctgc gctatgccaa gatgaagacggccaccaaca  901 tctacatcct aaatctggcc attgctgatg agctgctcat gctcagcgtgcccttcctag  961 tcacctccac gttgttgcgc cactggccct tcggtgcgct gctctgccgcctcgtgctca 1021 gcgtggacgc ggtcaacatg ttcaccagca tctactgtct gactgtgctcagcgtggacc 1081 gctacgtggc cgtggtgcat cccatcaagg cggcccgcta ccgccggcccaccgtggcca 1141 aggtagtaaa cctgggcgtg tgggtgctat cgctgctcgt catcctgcccatcgtggtct 1201 tctctcgcac cgcggccaac agcgacggca cggtggcttg caacatgctcatgccagagc 1261 ccgctcaacg ctggctggtg ggcttcgtgt tgtacacatt tctcatgggcttcctgctgc 1321 ccgtgggggc tatctgcctg tgctacgtgc tcatcattgc taagatgcgcatggtggccc 1381 tcaaggccgg ctggcagcag cgcaagcgct cggagcgcaa gatcaccttaatggtgatga 1441 tggtggtgat ggtgtttgtc atctgctgga tgcctttcta cgtggtgcagctggtcaacg 1501 tgtttgctga gcaggacgac gccacggtga gtcagctgtc ggtcatcctcggctatgcca 1561 acagctgcgc caaccccatc ctctatggct ttctctcaga caacttcaagcgctctttcc 1621 aacgcatcct atgcctcagc tggatggaca acgccgcgga ggagccggttgactattacg 1681 ccaccgcgct caagagccgt gcctacagtg tggaagactt ccaacctgagaacctggagt 1741 ccggcggcgt cttccgtaat ggcacctgca cgtcccggat cacgacgctctgagcccggg 1801 ccacgcaggg gctctgagcc cgggccacgc aggggccctg agccaaaagagggggagaat 1861 gagaagggaa ggccgggtgc gaaagggacg gtatccaggg cgccagggtgctgtcgggat 1921 aacgtggggc taggacactg acagcctttg atggaggaac ccaagaaaggcgcgcgacaa 1981 tggtagaagt gagagctttg cttataaact gggaaggctt tcaggctacctttttctggg 2041 tctcccactt tctgttcctt cctccactgc gcttactcct ctgaccctccttctattttc 2101 cctaccctgc aacttctatc ctttcttccg caccgtcccg ccagtgcagatcacgaaatc 2161 attaacaact cattctgatc ctcagcccct ccagtcgtta tttctgtttgtttaagctga 2221 gccacggata ccgccacggg tttccctcgg cgttagtccc tagccgcgcggggccgctgt 2281 ccaggttctg tctggtgccc ctactggagt cccgggaatg accgctctccctttgcgcag 2341 ccctacctta aggaaagttg gacttgagaa agatctaagc agctggtcttttctcctact 2401 cttgggtgaa ggtgcatctt tccctgccct cccctgtccc cctctcgccgcccgcccgcc 2461 accaccactc tcactccacc cagagtagag ccaggtgctt agtaaaataggtcccgcgct 2521 tcgaactcca ggctttctgg agttcccacc caagccctcc tttggagcaaagaaggagct 2581 gagaacaagc cgaatgagga gtttttataa gattgcgggg tcggagtgtgggcgcgtaat 2641 aggaatcacc ctcctactgc gcgttttcaa agaccaagcg ctgggcgctcccgggccgcg 2701 cgtctgcgtt aggcagggca gggtagtgca gggcacacct tccccggggttcggggttcg 2761 gggttcggtt gcagggctgc agcccgcctt ggctttctcc ctcacccaagtttccggagg 2821 agccgaccta aaagtaacaa tagataaggt ttcctgctcc agtgtatctcaaaagaccgg 2881 gcgccagggg cgggggacct agggcgacgt cttcagagtc cgccagtgttggcggtgtcg 2941 ccgcaacctg caggctcccg agtggggcct gcctggtctc tagagggttgctgcctttca 3001 agcggtgcct aagaagttat tttcttgttt aacatatata tttattaatttatttgtcgt 3061 gttggaaaat gtgtctctgc tttccttttc tctgcttgcc tagccccaggtcttttcttt 3121 gggaccctgg gggcgggcat ggaagtggaa gtaggggcaa gctcttgccccactccctgg 3181 ccatctcaac gcctctcctc aatgctgggc cctcttatct catcctttcctctagctttt 3241 ctatttttga ttgtgttgag tgaagtttgg agatttttca tacttttcttactatagtct 3301 cttgtttgtc ttattaggat aatacataaa tgataatgtg ggttatcctcctctccatgc 3361 acagtggaaa gtcctgaact cctggctttc caggagacat atataggggaacatcaccct 3421 atatataatt tgagtgtata tatatttata tatatgatgt ggacatatgtatacttatct 3481 tgctccattg tcatgagtcc atgagtctaa gtatagccac tgatggtgacaggtgtgagt 3541 ctggctggaa cactttcagt ttcaggagtg caagcagcac tcaaacctggagctgaggaa 3601 tctaattcag acagagactt taatcactgc tgaagatgcc cctgctccctctgggttcca 3661 gcagaggtga ttcttacata tgatccagtt aacatcatca ctttttttgaggacattgaa 3721 agtgaaataa tttgtgtctg tgtttaatat taccaactac attggaagcctgagcagggc 3781 gaggaccaat aattttaatt atttatattt catgtattga tttagtatgctggcttgtaa 3841 atagtaggca ctaaatacat gtttgttggt tgattgttta agccagagtgtattacaaca 3901 atctggagat actaaatctg gggttctaag gttcactcat tgacatgatatacaatggtt 3961 aaaatcacta ttgaaaaata cgttttgtgt atatttgctt caacaactttgtgctttcct 4021 gaaagaagta accaagagtt aagatatacc taatgttttg cttaaactaatgaacaaata 4081 tgctttgggt cataaatcag aaagtttaga tctgtccctt aataaaaatatatattacta 4141 ctcctttgga aaatagattt ttaatggtta agaactgtga aatttacaaatcaaaatctt 4201 aatcattatc cttctaagag gatacaaatt tagtgctctt aacttgttaaaattgtaata 4261 ttaactaaat aaacagatgt attatgctgt taaaaaaaaa aaaaaaaaaaaaaaaaaaaa 4321 aaaaaaaaaa aaaaaaaaaa aaa Rat Somatostatin Receptor Type1 mRNA (NCBI: NM_012719 (SEQ ID NO:18))    1 gctcgccaca gatgctgcgcgatgaaggga gggccaggcg cggtgagctg tgagcttgga   61 gcattgagcc tagggagggcgcaggcagca agggcgcaag gtgagcgtcc caaccggcgg  121 ccacaccggc ccacttcagctgggatgttc ccaaatggca ccgccccatc taccacatct  181 tctccaagct ccagcccaggaggctgcggg gaaggagtct gcagcagggg tcccgggtcc  241 ggcgctgcgg acggcatggaagaacctgga cgaaactctt cccagaacgg gactttaagc  301 gagggtcagg gtagcgccattctcatctct ttcatctact ccgtggtatg cttggtggga  361 ctgtgtggga actccatggtcatttacgtg atcctgcgct acgccaagat gaagaccgca  421 accaacatat acattctaaacctggccatt gctgatgagc tgctcatgct cagcgtgcca  481 tttctggtca cttacacgctgttgagccac tggccctttg gcgcgctact ttgccgcctg  541 gtgctcagcg tggatgcagtcaacatgttc accagcatct actgtctgac tgtgcttagt  601 gtggaccgct atgtggctgtggtgcacccg atcaaggcag cgcgctaccg tcggaccact  661 gtggccaaag tagtgaacctgggcgtgtgg gtgctgtcgc tactggttat cttgcccata  721 gtggtcttct cacgcaccgcagccaacagc gatggcacgg tggcctgcaa catgctcatg  781 cccgagcccg cccagcgctggttggtgggc ttcgtcttat acacatttct catgggcttc  841 ctgctgcctg tcggggccatctgcctgtgt tacgtgctca tcattgcaaa gatgcgcatg  901 gtggccctca aggccggctggcagcagcgc aagcgctcag agcgcaagat cactctaatg  961 gtgatgatgg tggtgatggtttttgtcatc tgctggatgc ctttctacgt ggtacagcta 1021 gtcaacgtgt tcgccgagcaagacgacgcc acggtgagcc agttgtctgt catactcgga 1081 tatgccaata gctgtgccaaccccatcctc tacggcttcc tgtcggacaa cttcaagcgc 1141 tctttccagc gcatcctgtgcctcagctgg atggataacg ctgcggagga gcctgttgac 1201 tactacgcca ctgccctgaagagtcgtgcc tacagtgtgg aggacttcca gcctgagaat 1261 ctggaatctg gaggcgttttccgtaatggc acctgcgctt ccaggatcag cacgctttga 1321 ggccggacgc taaccggagggggagagtgg tcagaaaggt ggagagggga agcaggtggg 1381 agggaatgat agccgcacaccaggtgctat gggagtagtg cgtgacagcg atgcagcgcc 1441 cctgtttagc aaagctatgtgactaaggta aacgggagag atttgagaat gttttcgggc 1501 catctggtat tctgaactgtgttctccaaa cccgataatt tccatcctcc ctcccagttc 1561 tgctagtaca aactgcaaacttaacgtcgc caactccgtt tgaccctttc cctctcaagc 1621 tgttatttct gcttctttaaactgagccat cttgtgtttc ttttgggctg agtccccacc 1681 ttgcgctgaa ccccctgcgcaggtcagcgg gccagactct tcagagcggc taccagactg 1741 tccccagtta ccgctccccttttgcacagc cttactgtca agtaagccca gatccaggat 1801 gaccaggcaa ctggtcttttctactctcaa agaaggcacc atcttccctt gggccctttc 1861 tctgcttcac tgcatccagagcagagctgg gtgcttaaga aaaagtcctg tgcccagatg 1921 gccagacttg gtgtagtcccacccattccc tcctttggag cacaaaaagg agctaagagc 1981 cagcagaagg gcaagtttctaagattcctg ggctgtggtt gtgggtgcca gagaagccac 2041 cctcccatag agctcaggacctgagcacta ggcttggagg tcccagctag gggagctccc 2101 ggcttgtgaa taacttatgcaccctggtgt gtgaacctga attgcacagc agttcccctt 2161 ggaggtctcc ctagaataacaaaggattgg gttgcctgct ccctttccta gtccagctcc 2221 tgttcaagtg acaaaccgcagagcccttgc caaagctgga tggctaactt cagcttgtct 2281 ggtccctgac attttttgcctttcaagcgg tgcctaataa gttatttctt gtttgacata 2341 tttatttatt tatttatggtgttgaaaaaa aaagtgtgtt tccactttct ttttctgtat 2401 ttgcctaaca gggctgttcttgagaatcct ctggcaggca cgtggtggtg tggaggtgtg 2461 gaggggagca ggggtggagaaagttctctc accccaagac tccctcagaa gtttcccttc 2521 ttttgcactc cattggccttttcttgatcc ttcttggttt tgcttgtgtc cagtgaagtt 2581 tggagatttt aaaaatatatttttactgta gttttgtctt gttaaaataa gtacatggca 2641 atttggttta acttttgtcagtgtggagtg gaaggcctga atccctggca tcccagaaaa 2701 cacaggggaa caaatcacatgatccgtgat gtatgtctgt atatgtgctg tcacacacaa 2761 gtcacatata tacgtgtatatatatatcat atatgtacac acacatataa aggtagattt 2821 gtcaatcttg acaactgtcactagttcatg aca˜ttataa ggacacccac aatgtgtgac 2881 ctgagctgta gcactccagctgggatctga gaaacgtcag agattggagt cgctgctgaa 2941 gatgctgctg cccttttctatcccctcaga ggtgattctt acccagtaag tctagtcact 3001 tttgttgagg aatggaagcgaaacaattgt gtctgcattt actgactacc gtggaaacct 3061 gaacacggaa ggacccatctcttcacttgt tgcatttgct gtgttcctgt gtatgctcgt 3121 ttgtacatag gggccactgaaaggatatct tgattggttg tttaaggaag caagtgtata 3181 tcagtggtct tagaacaatgaacctggggt tctcgggtcc acagtgacct gacatctaac 3241 ctgcaatggt cgaatgcactgttgaaaatg gtgttttgtg tacatttgct tcaagaacac 3301 atccatgctt ttcctaaaagcaggaaccaa gagttaaact gtctcttctg ttttgtttaa 3361 ataaatgaac aaatatgcttttgatcataa gtgagaaagt ttagatcttt tcctaagaat 3421 agtatatata tatatatatatgtatatata tatatatata tatgtatata tatatacttt 3481 tctgttaatt agattttttaaccgataaga agagtgaact ttataaactg aaatctccat 3541 cattatcata tagacaggataaaaatgtag tgctcttacc ctgtaatagt aactgaataa 3601 aaagatgtat tatgc HumanSomatostatin Receptor Type 2 mRNA (NCBI: NM_001050 (SEQ ID NO:19)) Onchromosome 17q24    1 cgcagccacc catgcgcgcg cgctcgcaag accaccagcgcacagagccc cagtctgagg   61 cttggcgccg ggggtctgcg ggcgagggga gctctctacgtgcgaggggc tagcgggagc  121 cggcacaaga gggtcgagga gccaggaacc ccaaacgtccggcgccaggc gctagccaag  181 ctgctgcgcg ccccggcgcc cagctggctc ggggacagccgctgggtgtc ggagaccgga  241 gctagcggat tgcagcggaa aagcaaagat gtcacactggatccttggcc tccagggtcc  301 attaaggtga gaataagatc tctgggctgg ctggaactagcctaagactg aaaagcagcc  361 atggacatgg cggatgagcc actcaatgga agccacacatggctatccat tccatttgac  421 ctcaatggct ctgtggtgtc aaccaacacc tcaaaccagacagagccgta ctatgacctg  481 acaagcaatg cagtcctcac attcatctat tttgtggtctgcatcattgg gttgtgtggc  541 aacacacttg tcatttatgt catcctccgc tatgccaagatgaagaccat caccaacatt  601 tacatcctca acctggccat cgcagatgag ctcttcatgctgggtctgcc tttcttggct  661 atgcaggtgg ctctggtcca ctggcccttt ggcaaggccatttgccgggt ggtcatgact  721 gtggatggca tcaatcagtt caccagcatc ttctgcctgacagtcatgag catcgaccga  781 tacctggctg tggtccaccc catcaagtcg gccaagtggaggagaccccg gacggccaag  841 atgatcacca tggctgtgtg gggagtctct ctgctggtcatcttgcccat catgatatat  901 gctgggctcc ggagcaacca gtgggggaga agcagctgcaccatcaactg gccaggtgaa  961 tctggggctt ggtacacagg gttcatcatc tacactttcattctggggtt cctggtaccc 1021 ctcaccatca tctgtctttg ctacctgttc attatcatcaaggtgaagtc ctctggaatc 1081 cgagtgggct cctctaagag gaagaagtct gagaagaaggtcacccgaat ggtgtccatc 1141 gtggtggctg tcttcatctt ctgctggctt cccttctacatattcaacgt ttcttccgtc 1201 tccatggcca tcagccccac cccagccctt aaaggcatgtttgactttgt ggtggtcctc 1261 acctatgcta acagctgtgc caaccctatc ctatatgccttcttgtctga caacttcaag 1321 aagagcttcc agaatgtcct ctgcttggtc aaggtgagcggcacagatga tggggagcgg 1381 agtgacagta agcaggacaa atcccggctg aatgagaccacggagaccca gaggaccctc 1441 ctcaatggag acctccaaac cagtatctga actgcttggggggtgggaaa gaaccaagcc 1501 atgctctgtc tactggcaat gggctcccta cccacactggcttcctgcct cccacccctc 1561 acacctggct tctagaatag aggattgctc agcatgagtccaattcagag aacggtgttt 1621 gagtcagctt gtctgattga atgataatgt gctaaattgattacctcccc cttaaagcga 1681 acactgaaat gcaggtagac aattcaaagt ctggagaagagggatcatgc ctggatatga 1741 tctttagaaa caacaaaaat agaaaaaaat aagtatctgtgtgtttgtgt attgaaaact 1801 caatatgtaa tcttgtgttt ttatatgtat acttgtatattcctatttat tctctgtata 1861 ggcattacct acgttcctgt gtttacatac acaagtagcaaattcgagta tgcatagtgt 1921 agatggacat ttgccacaac acactgcccg cagaaatggacttaccgtga agccaataaa 1981 gttcaagctt cagggatctc tcttgcacgg gccttgccaaggcccaggag ggacttgggc 2041 agtatgttca tgtggtcata tgtttttgta aaaaattgtgaaagtaagat atgtttgtat 2101 tgtttttctt aaagaggaac ctcgtataag cttcaagcctcacaaacctt ctagcctctg 2161 cccttgggga tttgcttcat taatttcagg caagtgaggtcaatgtaaga agggaaaggg 2221 agaagatatt tgaagaacca gaatgtaaat tcatgtgtttccacttctca gatatagtca 2281 gagaattatt catttgccca aaaggactta agtggttgtggtcatccatc attgtattta 2341 tcaagacaaa gccaactttg ttataagatt gcatttttttcttttcaaat tgctttagtt 2401 tttcttaggg agctatgagg gggaaaaatc actaacatgaaaggcaaaaa atggactatg 2461 attcctgtgg ggaaacaatt tcattctctc catcgtgaaaataagtgaat aagagtgaag 2521 caaaattaca cctttatgag aaaccataaa attgtttttatttttcaggc cagacatagc 2581 ttcctaatga aagaaaatgg aaatgtaatt cgacgactcctcaaagggga ctttagagga 2641 cttcatacaa agctgggcat taagaaaacc acaatgcatggccgggcgtg gtggcttaca 2701 cctgtaatcc cagcactttg ggaggccgag gtgggtggatcacccgaggt caggagttcg 2761 agaccagcct ggccaacatg gtgaaacccc atcactactaaaaatatgta aattagtcgg 2821 gcgtggtgtc acgtgcctgt aatcctagct gctcgggaggctgaggcagg agaatcactt 2881 gaacttggga ggtggaggtt gcagtaagct gagattgtgccactgcactc tagcctgagc 2941 aacaagagca aaactcagtc tcaaaaaaaa aaaaaaaaaaaaaaaaaaaa aaaaaa Rat Somatostatin Receptor Type 2 mRNA (NCBI: NM_019348(SEQ ID NO:20))    1 gacaccggca cgctggcgag gccaccggcc ctggagcaccagtccgccga tgggcgtcga   61 tgatctacag gccagggtag ctctactggg gcccaggcaagctctctcag acgccaggag  121 ggacagcacg agccagactg ggaagctgcg agccagagagctactgcgga gcgccaaaca  181 ccccctaaac ctgctgcgct aacgggcgcc cggatgggtaaaggacagat tctgggagct  241 agagaacaca gagaagagag tgctcgtgga aaagaaagatgtcacgatag acccttggcc  301 ccagagtcca ctgaggtgag aggaagatct ctgggctgcttggttctagg cggaatgaag  361 agcagaaatg gagttgacat ctgagcagtt caatgggagccaagtgtgga taccttctcc  421 ctttgacctc aacggctcac tggggccaag caatggctccaaccagacag agacatacta  481 cgacatgaaa agcaacgcgg tcataacgtt aatctacttcgtggtgtgcg tggtggggat  541 gtgcggcaac acgctagtca tctacgtcat catccgatacgccaagatga aaaccatcac  601 caacatttaa atcctcaacc tggccatcgc agatgaactcttcatgctgg ggatgccctt  661 cttggcaatg caggtggagc tggtccactg gccttttggcaaggccatct gccgggtggt  721 catgactgtg gacggtatca accagttcac cagtatcttctgcttgacgg tcatgagcat  781 cgaacgttac ctggccgtgg tacaccccat taagtcagcaaaatggaggc gaccccggac  841 agccaagatg atcaacgtgg ctgtgtgggg tgtgtccctgcttgtcattt tgcccatcat  901 gatatacgct ggcctccgga gcaaccagtg gggtaggagcagctgcacca tcaactggcc  961 gggcgaatcc ggggcatggt acacgggttt cattatctatgccttcatcc tggggttcct 1021 ggtaccccta accatcatat gtctctgcta cctgttcatcatcatcaagg tgaagtcctc 1081 tgggatccga gtggggtcgt ccaagaggaa aaagtcagagaaaaaggtga cccgaatggt 1141 atccatcgtg gtggctgtct tcatcttctg ctggctccccttctatatct tcaatgtctc 1201 gtccgtgtct gtggcaatca gccccaccac tgccctgaaaggcatgtttg actttgtggt 1261 tatcctcacc tacgccaaca gctgcgccaa ccccatcatgtacgccttct tgtccgacaa 1321 cttcaagaag agcttacaga atgttctttg cttggtcaaggtgagtggtg cggaggatgg 1381 ggagcggagc gacagtaagc aggacaaatc ccggatgaatgagaccacgg agacccagag 1441 gaccctacta aatggagacc tccaaaccag tatctgaaacaacccgggaa cgcaacgtga 1501 acacgcacta gccaagcccc gcctcctggc agtgcgagccccattcaccc gattcctgcc 1561 tacactaccc atcacaccag gcttttctag agcagagcggatttgagtct ggcttgtccg 1621 aaagtatacc cctctggtca catatacacc taaagtgaacgttttcgtgc aggcagacaa 1681 ttcaaagact ggagaagagg acacgatggc ctgggtgtgacccggtggaa agcagataca 1741 cggcagaaac cggaaaaacc aaaactaaaa tcaaagttccgcgcgtgtac gtgtgcttgc 1801 ccgctatgta atatcgtgat ctgatatttc cgtttgtacatcacctcccc acccacacac 1861 cggtctctgc ggagccagta tacacgtgtc ctgtgtttgtaaacccaagt agctagttca 1921 tgtgcgtcta gtataggtgg acatttacca cagcgctgaacctgacgaca aggactcacc 1981 atgtcagagt caatctaatc taagcttcca gcatccctcttgcatgggcc tttcccagac 2041 ccaggaggag catgagcagt atgttcatat aataatacatttttgtaaaa agaaaaaaaa 2101 aaaaaaaaaa aaaaaa Human Somatostatin ReceptorType 3 mRNA (NCBI: NM_001051 (SEQ ID NO:21))    1 cgcatctctc atcactacacctcattctgc ctttcctcct actcacggtc tcctctccct   61 ctccctctct ctctctccccctccctcttt ctctctctct ctctttctcc acctcctaca  121 gacccccttt cccctctatttctattggct tctgtgtccc ttgctcccct cttctcttcc  181 tcaccctggg aagcttctcccccctatcct tgcccctgcc cacccaggat gtgtcctgga  241 gatggggggt gacgtaccaggctctggttg ggaagtcagg gccggagacc agatgggaga  301 ggctctgtgg acagccgtggccgagggcct gggagggaac ctgagccagc aagcggtcta  361 gaagtgggtg ccgtgtggggaccctagtta ggagtgccct gggggcacct ggggactggg  421 cagggagagg ggacagcagaatgataacca gcctggcggc aaggagggaa gacctcaccc  481 catgggcagg caaatagctgactgctgacc accctcccat cagccatgga catgcttcat  541 ccatcatcgg tgtccacgacctcagaacct gagaatgcct cctcggcctg gcccccagat  601 gccaccctgg gcaacgtgtcggcgggccca agcccggcag ggctggccgt cagtggcgtt  661 ctgatccccc tggtctacctggtggtgtgc gtggtgggcc tgctgggtaa ctcgctggtc  721 atctatgtgg tcctgcggcacacggccagc ccttcagtca ccaacgtcta catcctcaac  781 ctggcgctgg ccgacgagctcttcatgctg gggctgccct tcctggccgc ccagaacgcc  841 ctgtcctact ggcccttcggctccctcatg tgccgcctgg tcatggcggt ggatggcatc  901 aaccagttca ccagcatattctgcctgact gtcatgagcg tggaccgcta cctggccgtg  961 gtacatccca ccagctcggcccgctggcgc acagctccgg tggcccgcac ggtcagcgcg 1021 gctgtgtggg tggcctcagccgtggtggtg ctgcccgtgg tggtcttctc gggagtgccc 1081 cgcggcatga gcacctgccacatgcagtgg cccgagccgg cggcggcctg gcgagccggc 1141 ttcatcatct acacggccgcactgggcttc ttcgggccgc tgctggtcat ctgcctctgc 1201 tacctgctca tcgtggtgaaggtgcgctca gctgggcgcc gggtgtgggc accctcgtgc 1261 cagcggcggc ggcgctccgaacgcagggtc acgcgcatgg tggtggccgt ggtggcgctc 1321 ttcgtgctct gctggatgcccttctacgtg ctcaacatcg tcaacgtggt gtgcccactg 1381 cccgaggagc ctgccttctttgggctctac ttcctggtgg tggcgctgcc ctatgccaac 1441 agctgtgcca accccatcctttatggcttc ctctcctacc gcttcaagca gggcttccgc 1501 agggtcctgc tgcggccctcccgccgtgtg cgcagccagg agcccactgt ggggcccccg 1561 gagaagaatg aggaggaggatgaggaggag gaggatgggg aggagagcag ggaggggggc 1621 aaggggaagg agatgsacggccgggtcagc cagatcacgc agcctggcac cagcgggcag 1681 gagcggccgc ccagcagagtggccagcaag gagcagcagc tcctacccca agaggcttcc 1741 actggggaga agtccagcacgatgcgcatc agctacctgt agggcctggg gaaagccagg 1801 atggcccgag gaagaggcagaagccgtggg tgtgcctagg gcctacttcc caaggtgcca 1861 caggcccatg atgggatgttgaggggcctg gactttgatg ctattgctgc caggtcttgc 1921 tgtgtgacct tgggtaggttgcttctactc tctgggcctt gttttctcct ctgtgactca 1981 gggataggag tcatcagactggatgagcta tgtcagatga gaggtttgga gggcactgtt 2041 gctgggctga cctggctgagcaggcaaaag gtgggtgcag actggcctcc ccacagggat 2101 ggagtgtctt ggggcatcaacta Rat Somatostatin Receptor Type 3 mRNA (NCBI: NM_133522 (SEQ IDNO:22))    1 caggcgtctc tccttactcc ccctcattct gcctttccgc ccacacactgtctcctctcc   61 ctctcctctc tctctctcca cctccgaccc tccccctcct ttccttattttcctcggcct  121 tcttatgtcc cctgctatct cacatttctg tcatctttgg aagtgccttctgtcaccccc  181 aactgggtgc catctgaaga cccccatcct gtgtccggca cccgccacgtgtcctggaga  241 tggggggtga cgtatcaggt gcgggtggca agtcaggact gaggaccagatgggagaggc  301 gacgtgggct gacgtggccc ccgaggacct aggaagggcc caaccaagcccacaagcact  361 ggaggagtgg gcactgtgtg tcaccccagc tggctgtgct ctggtggtacctggctgcag  421 aaggttatcc agcctggcga ctgcaaaggg aattcttgcc ctgtgggcagaatcttggaa  481 cctccatgca gcagaatgtc agaactggac caaagagatg caagctacccatggcttccc  541 aggccttgag caccccctca tgctggcagt ggtgcatctg aagagtcccttccacctttg  601 cagcaacccc gtaaggtttg ggctagttgg ctgctgactg atcctcatccctgccatggc  661 cgctgttacc tatccttcat ccgtgcctac gaccttggac cctgggaatgcatcctcagc  721 ctggcccctg gacacgtccc tggggaatgc atctgctggc actagcctggcaggactggc  781 tgtcagtggc atcttgatct ctctggtgta cctggtggtg tgtgtggtgggtttgctggg  841 caattcactg gtgatctacg tggttctgcg gcacacgtcc agcccatcagtgaccagtgt  901 atatatcctc aacctggcac tggctgacga actcttcatg ctggggctacctttcctggc  961 tgctcagaac gccctgtcct actggccttt cggctctctc atgtgtcgtctggtcatggc 1021 cgtggatggc atcaaccagt tcaccagcat cttctgcctc accgtcatgagtgtggaccg 1081 ctacctggct gtggtgcacc ccacacgctc tgaccgctgg cgcacggcacctgtggctcg 1141 aatggtcagt gcagctgtct gggtggcata agctgtggtc gtgctgcctgtggttgtgtt 1201 ctcaggagtg ccccgaggga tgagcacgtg ccacatgcag tggccagagccagcggctgc 1261 ctggcgaaca gccttcatca tctatacggc cgcactgggc ttttttgggcccctgctggt 1321 catctgctta tgctacctgc ttattgtggt gaaggtgcgg tcgaccacacggcgggtgcg 1381 ggcgccctcg tgccagtggg tacaggcacc cgcttgccag aggcggaggcgctctgagcg 1441 aagggtgaca cgcatggtgg tggctgtggt ggcactcttc gtcctctgctggatgccttt 1501 ctatttactc aacatcgtta atgtggtgtg cccgctgccg gaggagcccgccttctttgg 1561 cctctacttc ctggtggtcg cgctgcccta cgccaacagc tgcgcaaaccccatcctcta 1621 cggcttcctc tcctaccgct tcaagcaggg cttccgcagg atcctgctaagaccttctcg 1681 gcgagtacgg agccaggagc cagggtctgg cactacagag aagacggaggaggaggagga 1741 tgaagaggaa gaagagagaa gggaagagga agagcggagg atgcagagagggcaggagat 1801 gaatgggagg ctcagtcaga tagcacagcc aggccccagt ggacagcagcaacggccttg 1861 cacagggact gccaaggaac agcagcttct accccaggaa gccacagctggggacaaggc 1921 cagcacgctg agccatctgt aagaaccttc aaagagccag catgatcctgaagagagcag 1981 aagctatgct tgacctaagg cacgagtacc agacacatgg cagtgttctaagcaagcaac 2041 agctagagtg agcttattta catggctgtc ctggccctct ctggaccgttgtggtactag 2101 ggtccagtga tggaatgtcc ataggcctgg gctctgtccc actgtgccagggcttgctgt 2161 gtatactttg gccagtcact agccctctct gggtcttgtt ttcttcttttgactcaggga 2221 tgggtaaaat gagccctgtc agaagagggg tctggaatcc ttattgggattaatctccta 2281 atcagagcac aagttaagaa tttgcacagt ctgaccaaga aacaagatatcttggggatc 2341 agtctgtatc ttggccctca aggagataca ccagggcttg ggaaatcagagatgcagatg 2401 acctgggggt gggtgcttgg ctgaaaccta aaggaagtgt tagttggtgtggtgggatgc 2461 cacggcttag gacgcaagtg agccctttcc atgctgctct gtggcctcagccactctgtt 2521 catgtgcagg catcctacat cttctgcagg gcagtccggg tgtcctacagaccctcaccc 2581 cagcgtctga gcattgggcc ttctgtgctc ctggacacca ggggaagaacttcccagaag 2641 gcaggtgaaa ccaagtttca ggggttcttg ctgcttgggc ccccctgggacctacgtgtg 2701 actggtcttc taattttgta ttccttctct ggagggaaga ttgcacaccaccaggctcag 2761 gccaccagga gactgactca ccatattcag gtcagctacc tagtccccagggctatgcag 2821 cagcctgagg gaaggagagg gagaaaggag gagagggagc tgaggcagtaagaagaggag 2881 ggggatggga tcggagggag aagagaacag aactttgtgg tgatcttgagtcaaccttct 2941 cccccttgag ctaagctcag tttgcagcac tgatggtttc aggaaggatctgaaggagac 3001 atgtgaccag gatcccctgg agggtgcgtg gggctggtga gaggggcacaggtcatgatg 3061 gagtcgtggg aatgggcttg gctcctcagg agggatggta agtcctttgtgtgggtcagt 3121 cctaacatcc tctattccaa gggctccagc tgatgtagag actaacaggctgtcatgggg 3181 agtagccact gtcccagctg ggtcaggact tcattcttcc cctaccagagatggtcctta 3241 tggtaccagc agtgatggcc ctggaaaggt tgaggcttct gctcaaacccccaccctacc 3301 ctgcagaggc agggttctca gggaacccac aaatccagat gttgagaaagctggatcttc 3361 tattcacctc aagcctcttg gccataccct ctgtctctgc gcctcagtatcctcatcata 3421 gtgagaatgt gatcccccag ttctccagtc tgttagaata aaggagggaactgagtcatg 3481 caaggcaagc tactgctcac cacaatgggg ctgcgtaagg atacaaagcggccgtgttgt 3541 aaatcaggct cagcccacac cttgcccttt aagtgagtgg cttcggtgtcagctactgga 3601 ggtgaaggta ttcatgagaa atggagtgca ggaggtcaga agccaaggaccatggagaat 3661 gcaagccacc ccagaaggag gaagtttgca aacataggaa tgtatggggaatgaggccca 3721 gcacaggggt tcctctgaga aggagctggg tcaggaagta agcagtccaaccttcatgga 3781 tggggtaggt gagccacgta ttgcaaaggg gtgggtgacc agttgagaagttatttgctg 3841 cttctgacct gagctcctgt caataaagat agtgactaag aaaaaaaaaaaaaaaaaaaa 3901 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaaaaaaaaaaaa 3961 aaaaaaaaaa aaaaaaaaaa aaaaa Human Somatostatin ReceptorType 4 mRNA (NCBI: NM_001052 (SEQ ID NO:23))    1 atgagcgccc cctcgacgctgccacccggg ggcgaggaag ggctggggac ggcctggccc   61 tctgaagcca atgccagtagcgctacggcg gaggcggagg aggcggtggc ggggcccggg  121 gacgcgcggg cggcgggcatggtcgctatc cagtgcatct acgcgctggt gtgactggtg  181 gggctggtgg gcaacgccctggtcatcttc gtgatccttc gctacgccaa gatgaagacg  241 gctaccacca tctacctgctcaacctggcc gtagccgacg agatattcat gctgagcgtg  301 cccttcgtgg cctcgtcggccgccctgcgc cactggccct tcggctccgt gctgtgccgc  361 gcggtgctca gcgtcgacggcctcaacatg ttcaccagcg tcttctgtct caccgtgctc  421 agcgtggacc gctacgtggccgtggtgcac catctgcgcg cggcgaccta ccggcggccc  481 agcgtggcca agctcatcaacctgggcgtg tggctggcat ccctgttggt cactctcccc  541 atcgccatct tcgcagacaccagaccggct cgcggcggcc aggccgtggc ctgcaacctg  601 cagtggccac acccggcctggtcggcagtc ttcgtggtct acactttcct gctgggcttc  661 ctgctgcccg tgctggccattggcctgtgc tacctgctca tcgtgggcaa gatgcgcgcc  721 gtggccctgc gcgctggctggcagcagcgc aggcgctcgg agaagaaaat caccaggctg  781 gtgctgatgg tcgtggtcgtctttgtgctc tgctggatgc ctttctacgt ggtgcagctg  841 ctgaacctcg tcgtgaccagccttgatgcc accgtcaacc acgtgtccct tatcctcagc  901 tatgccaaca gctgcgccaaccctattctc tatggcttcc tctccgacaa cttccgccga  961 tccttccagc gggttctctgcctgcgctgc tgcctcctgg aaggtgctgg aggtgctgag 1021 gaggagcccc tggactactatgccactgct ctcaagagca aaggtggggc agggtgcatg 1081 tgccccccac taaaatgccagcaggaagcc ctgcaaccag aacccggccg caagcgcatc 1141 cccatcacca ggaccaccaccttctga Rat Somatostatin Receptor Type 4 mRNA (NCBI: NM_013036 (SEQ IDNO:24))    1 gttcagcgtt cggctgctct ccacggcaat ccgctgcccc gggtgggcaccccgaagcat   61 gaacacgcct gcaactctgc ccctgggggg cgaggacacc acctggacccctgggatcaa  121 cgccagctgg gctccggatg aggaggagga tgcagtgcgg tccgacggcacggggacagc  181 gggcatggta actatccagt gcatctatgc gctcgtgtgt ctggtgggcctggtaggaaa  241 cgccctggtc atattcgtga tcctacgcta tgccaaaatg aagacagccaccaacatcta  301 cctgctcaac ctggccgtcg ctgatgagct cttcatgctc agtgtgccatttgtggcctc  361 ggcggctgcc ctgcgccact ggccgttcgg ggcggtgctg tgccgcgcagtgcttagtgt  421 ggacggcctt aacatgttca cgagtgtctt ctgcctcaca gtgctcagcgtggatcgcta  481 tgtggctgta gtgcaccctc tgcgagctgc cacctaccgg cggcccagcgtggccaagct  541 aatcaacctg ggagtgtggc tagcatcctt gctggtcacc ctgcccatcgcagtcttcgc  601 tgacactagg ccagctcgtg ggggtgaggc agtagcttgc aacctgcactggcctcaccc  661 ggcctggtct gcagtctttg tgatctatac ttttttgctg ggcttcctactcccggttct  721 ggctatcgga ttatgttacc tgcttatcgt gggcaagatg cgtgctgtggccctgcgggc  781 tggctggcaa caacggaggc gctcagagaa gaagatcact aggctcgtgctaatggtggt  841 gactgtcttt gtgctatgct ggatgccatt ctatgtagtg cagcttctgaatctgtttgt  901 caccagcctc gatgccactg tcaaccatgt gtccctcatc ctcagctatgccaacagctg  961 tgccaacccg attctctatg gtttcctctc agacaacttc cgacgctctttccagcgggt 1021 tctgtgcctg cgctgctgtc tcctggaaac aactggaggt gctgaggaagagcccctgga 1081 ctactatgct actgctctca aaagcagagg tggcccagga tgcatatgccctccattgcc 1141 ctgccagcag gagcccatgc aagcagaacc tgcctgcaag cgagtccctttcaccaagac 1201 cactactttc tgaaaaccat ttcaccctcc ctcagcccac ctgcaagcaggtctgcacca 1261 cactctcaag ccagcaactt caagaaaact cctgttgtca ctaagccaggccctttcagc 1321 agcctgtgtt ctgtccctag gagcctcagg actcctgcta gcccctgcctctcctaggac 1381 tgactggatc caaggacaac tccgtggggg taggacttct ctgggttttgggctagagta 1441 ccatccatcc tttcatggac atctagcaat ttttcaagag gcaggaagcaggtggtggta 1501 agaaagggat gcctaccctt gtgtgaattg tgacagtgac tgcttggaagagcgctggga 1561 gggtgaggta ggcagagcta ggctctctgc tgtgtggtag catagggcatacggtgatac 1621 aggggagaag atatgatacc taaaagtgtt ttccatctgt gtatgtctgagtctcttgtt 1681 gctaaatgag atgtctaagc aacagctgaa agcatttgct ttcccaaggcaaatgtttct 1741 ccagttgtca aaggaccagt agcagacttc ctgagaatgc aaatgtttaaagaaggatgg 1801 tgtggggcgt tttttgaaaa aaaaaataat tctgatttct ggtcaggaattaaaaggcag 1861 aaagg Human Somatostatin Receptor Type 5 mRNA (NCBI:NM_001053 (SEQ ID NO:25))    1 atggagcacc tgttcccagc ctccacgccaagctggaaag cctcatcccc gggggctgcc   61 tatggaggcg gtgacaacag gacgatggtggggccggcgc cctcggcagg ggcccgggcg  121 gtgctggtgc cagtgctgta cctgatggtgtgtgcggccg ggctgggcgg gaacacgctg  181 gtcatctacg tggtgctgcg cttcgccaagatgaagaccg tcaccaacat ctacattatc  241 aacctggcag tggccgacgt cctgtacatgctggggctgc ctttcctggc cacgcagaac  301 gccgcgtcct tctggccctt cggccccgtcctgtgccgcc tggtcatgac gctggacggc  361 gtcaaccagt tcaacagtgt cttctgcctgacagtcatga gcgtggaccg ctacctggca  421 gtggtgcacc agctgagctc ggcccgctggcgccgcccgc gtgtggccaa gctggcgagc  481 gccgcggcct gggtcctgtc tctgtgcatgtcgctgccgc tcctggtgtt cgcggacgtg  541 caggagggcg gtacctgcaa cgccagctggcaggagcccg tggggctgtg gggcgccgtc  601 ttcatcatct acacggccgt gctgggcttcttcgcgccgc tgctggtcat ctgcctgtgc  661 taactgctca tcgtggtgaa ggtgagggcggcgggcgtgc gcgtgggctg cgtgcggcgg  721 cgctcggagc ggaaggtgac gcgcatggtgttggtggtgg tgctggtgtt tgcgggatgt  781 tggctgccct tattcaccgt caacatcgtcaacctggccg tggagctgcc ccaggagccc  841 gcctccgccg gcctctactt cttcgtggtcatcctctcct acgccaacag ctgtgccaac  901 cccgtcctct acggcttcct ctctgacaacttccgccaga gcttccagaa ggttctgtgc  961 ctccgcaagg gctctggtgc caaggacgctgacgccacgg agccgcgtcc agacaggatc 1021 cggcagcagc aggaggccac gccgcccgcgcaccgcgccg cagccaacgg gcttatgcag 1081 aaaagcaagc tgtga Rat SomatostatinReceptor Type 5 mRNA (NCBI: NM_012882 (SEQ ID NO:26))    1 ccgacttcgtacagcaatcg agtgagcaca ctgatctttg agcccgagtg cgctgcctaa   61 ctgcgaagtaccgccgccgt gcccgccccg gcgtgggcac cctgtcctgc acagagacac  121 gcgtggtctggcacccggcc tgaagctgac agcatggaga ccctctctat ggcctccaca  181 ccaagctggaatgcctcggc tgcttccagt ggtaaccata actggtcact ggtgggctca  241 gcatcgccaatgggagcccg ggcagtatta gtgcctgtgc tctacctgtt ggtgtgcacc  301 gtgggactgagtggaaataa actggtcatt tatgtggtgc tgcggcacgc caagatgaag  361 acagttactaacgtgtacat cctgaacctg gccgtggctg acgtattatt tatgttggga  421 cttcctttcctggccacgaa gaacgacgta gtctcctact ggcccttcgg ctccttcttg  481 tgccgcctggtcatgacact ggatggcatc aaccagttca ccagtatctt ctgcctgatg  541 gtcatgagtgttgaccgcta cctggccgtg gtccaccctc tacgctcagc ccggtggcgt  601 cgcccacgggtagccaagat ggccagcgcg gccgtctggg tcttttcgct gctcatgtct  661 ctgccgctcttggtcttcgc ggatgtccag gagggctggg gcacctgcaa cctgagatgg  721 ccagagcctgtggggctgtg gggtgcagcc ttcatcacct acaagtctgt gttgggcttc  781 tttgggccactgctggtcat ctgcttgtgc tacctgctca ttgtggtcaa ggtgaaggct  841 gcaggcatgcgagtaggctc ctcaaggcgg aggcgctcgg agccgaaggt gactcgcatg  901 gtggtggtcgtggtgctggt gtttgtgggc tgctggctgc ctttcttcat tgtcaacatc  961 gtcaacctggccttcacact gcccgaggaa cccacatatg ccggcctcta tttctttgtg 1021 gtggtcctatcttatgccaa tagctgtgcc aaccccctgc tctacggctt tctctcggac 1081 aacttccgccagagcttccg gaaggttctg tgcctacgta gaggatacgg tatggaggat 1141 gcggacgccatagagccacg gccagacaag agtgggcggc ctcaggccac actgcccaca 1201 cgcagctgcgaggccaatgg gctcatgcag accagcagga tttgaatgcc cctgtaacac 1261 cctgggggtcctccaggcct ccacggtgtt gtcttctggg atctgagagt ttgatgagat 1321 gcattcacccccaggcctac aagttggact cctctcggtg gcagtgtgaa gacaggacct 1381 gcag

TABLE 6 List of Disclosed Peptide Based Somatostatin ReceptorAntagonists and Structures Seq ID Other No. Peptide code Names StructureRef.  27 AC 178, 335 Ac-His-Phe-Ile-Arg-Trp-Phe-NH2 49, 51, 52  28BIM-23458 DC-41-33, H-Fpa-cyclo[DCys-Pal-DTrp-Lys-Tle-Cys]-Nal-NH2 27,28, PRL-2903 51, 54, 55, 56  29 BIM-23627H-p-Chloro-DPhe-cyclo[DCys-Pal-Trp-Lys-Val-Cys]-2-Nal-NH2 49, 52, 56  30CYN 154806 D-Tyr8 Ac-4-NO2-Phe-cyclo[DCys-Tyr-DTrp-Lys-Thr-Cys]-DTyr-NH249, 57, 59  31 CYN 154806 L-Tyr8Ac-4-NO2-Phe-cyclo[DCys-Tyr-DTrp-Lys-Thr-Cys]-LTyr-NH2 49, 57, 59  32PRL-2915 H-Cpa-cyclo[DCys-Pal-DTrp-Lys-Tle-Cys]-Nal-NH2 53, 60  33PRL-2970 H-Cpa-cyclo[DCys-Tyr-DTrp-Lys-Thr-Cys]-Nal-NH2 49, 53, 60  34BIM-23454 H-Cpa-Cys-Pal-Trp-Lys-Val-Cys-Nal-NH2 51, 56, 61, 62  35cyclo- cyclo[Ahp-Phe-DTrp-Lys-Thr-(Bzl)] 51, 58, somatostatin 68  36DC-38-48 H-Nal-cyclo[DCys-Pal-DTrp-Lys-Val-Cys]-Nal-NH2 53  37 PRL-2876H-Nal-cyclo[DCys-Pal-DTrp-Lys-Gly-Cys]-Nal-NH2 53  38 PRL-2874H-Nal-cyclo[DCys-Pal-DTrp-Lys-Ala-Cys]-Nal-NH2 53  39 PRL-2877H-Nal-cyclo[DCys-Pal-DTrp-Lys-Leu-Cys]-Nal-NH2 53  40 PRL-2879H-Nal-cyclo[DCys-Pal-DTrp-Lys-Nle-Cys]-Nal-NH2 53  41 PRL-2875H-Nal-cyclo[DCys-Pal-DTrp-Lys-Tle-Cys]-Nal-NH2 53  42 PRL-2889H-Nal-cyclo[DCys-Pal-DTrp-Lys-Tle-Cys]-Nal-NH2 53  43 PRL-2900H-Nal-cyclo[DCys-Bta-DTrp-Lys-Val-Cys]-Nal-NH2 53  44 PRL-2891H-Nal-cyclo[DCys-3ITyr-DTrp-Lys-Val-Cys]-Nal-NH2 53  45 PRL-2908H-Trp-cyclo[DCys-Pal-DTrp-Lys-Tle-Cys]-Nal-NH2 53  46 PRL-2882H-Fpa-cyclo[DCys-Pal-DTrp-Lys-Val-Cys]-Nal-NH2 53  47 PRL-2904H-DFpa-cyclo[DCys-Pal-DTrp-Lys-Tle-Cys]-Nal-NH2 53  48 PRL-2910H-Cpa-cyclo[DCys-Pal-DTrp-Lys-Val-Cys]-Nal-NH2 53  49 PRL-3020H-Cpa-cyclo[DCys-Pal-DTrp-Lys-Thr-Cys]-Nal-NH2 53  50 PRL-3052H-Cpa-cyclo[DCys-Pal-DTrp-Lys-Tba-Cys]-Nal-NH2 53  51 PRL-3023H-Cpa-cyclo[DCys-2Pal-DTrp-Lys-Thr-Cys]-Nal-NH2 53  52 PRL-3024H-Cpa-cyclo[DCys-D2Pal-DTrp-Lys-Thr-Cys]-Nal-NH2 53  53 PRL-2972H-Cpa-cyclo[DCys-Phe-DTrp-Lys-Thr-Cys]-Nal-NH2 53  54 PRL-2894 SB-710411H-Cpa-cyclo[DCys-Pal-DTrp-Lys-Val-Cys]-Cpa-NH2 51, 53  55 PRL-2859H-Fpa-cyclo[DCys-Pal-DTrp-Lys-Val-Cys]-Fpa-NH2 53  56 PRL-2872H-Fpa-cyclo[DCys-His-DTrp-Lys-Val-Cys]-Fpa-NH2 53  57 PRL-2888H-DFpa-cyclo[DCys-Pal-DTrp-Lys-Val-Cys]-DFpa-NH2 53  58 PRL-2858H-3Fpa-cyclo[DCys-Pal-DTrp-Lys-Val-Cys]-3Fpa-NH2 53  59 PRL-2869H-3Fpa-cyclo[DCys-His-DTrp-Lys-Val-Cys]-3Fpa-NH2 53  60 PRL-2857H-2Fpa-cyclo[DCys-Pal-DTrp-Lys-Val-Cys]-2Fpa-NH2 53  61 PRL-2868H-2Fpa-cyclo[DCys-His-DTrp-Lys-Val-Cys]-2Fpa-NH2 53  62 PRL-2917H-Cpa-cyclo[DCys-Pal-DTrp-Lys-Tle-Cys]-Cpa-NH2 53  63 PRL-2918H-DCpa-cyclo[DCys-Pal-DTrp-Lys-Tle-Cys]-DCpa-NH2 53  64 PRL-2905H-Bpa-cyclo[DCys-Pal-DTrp-Lys-Val-Cys]-Bpa-NH2 53  65 PRL-2907H-Iph-cyclo[DCys-Pal-DTrp-Lys-Val-Cys]-Iph-NH2 53  66 PRL-2856H-Pfp-cyclo[DCys-Pal-DTrp-Lys-Val-Cys]-Pfp-NH2 53  67 PRL-2862H-Pfp-cyclo[DCys-His-DTrp-Lys-Val-Cys]-Pfp-NH2 53  68 PRL-3064H-Pfp-cyclo[DCys-2Pal-DTrp-Lys-Val-Cys]-Pfp-NH2 53  69 PRL-2855H-Pfp-cyclo[DCys-D2Pal-DTrp-Lys-Val-Cys]-Pfp-NH2 53  70 PRL-2870H-Bip-cyclo[DCys-Tyr-DTrp-Lys-Ile-Cys]-Bip-NH2 53  71 PRL-2902H-Ypa-cyclo[DCys-Pal-DTrp-Lys-Val-Cys]-Ypa-NH2 53  72 PRL-2896H-Igl-cyclo-[DCys-Pal-DTrp-Lys-Val-Cys]-Igl-NH2 53  73 PRL-2878H-Tic-cyclo[DCys-Tyr-DTrp-Lys-Val-Cys]-Tic-NH2 53  74 PRL-2897H-Nal-cyclo[DCys-Pal-DTrp-Lys-Val-Cys]-DDip-NH2 53  75 PRL-2898H-Nal-cyclo[DCys-Tyr-DTrp-Lys-Val-Cys]-DDip-NH2 53  76 PRL-2883H-Nal-cyclo[DCys-Pal-DTrp-Lys-Val-Cys]-Fpa-NH2 53  77 RJ-01-48cyclo[NmeDAla-Tyr-DTrp-Lys-Val-Phe] 60  78 NC-11-31H-Ala-Gly-cyclo[Cys-Lys-Asn-DPhe-Phe-DTrp-Lys-Thr-Phe- 60Thr-Ser-Cys]-OH  79 DC-38-28 H-Phe-DPhe-Tyr-DTrp-Lys-Thr-Phe-Thr-NH2 60 80 DC-38-25 H-DPhe-DPhe-Tyr-DTrp-Lys-Thr-Phe-Thr-NH2 60  81 DC-38-45H-Phe-DCpa-Tyr-DTrp-Lys-Val-Phe-Thr-NH2 60  82 DC-8-42H-Nal-DCpa-Tyr-DTrp-Lys-Val-Phe-Thr-NH2 60  83 DC-32-15H-DNal-DCpa-Tyr-DTrp-Lys-Val-Phe-Thr-NH2 60  84 DC-38-73H-Nal-DCpa-Tyr-DTrp-Lys-Val-Phe-Nal-NH2 60  85 DC-38-76H-DNal-DCpa-Tyr-DTrp-Lys-Val-Phe-Nal-NH2 60  86 DC-38-58H-Nal-cyclo[DCys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2 60  87 BIM-23246H-DNal-cyclo[DCys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2 60  88 DC-38-61(NH2)-Phe-cyclo[DCys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2 60  89 DC-38-55Ac-cyclo[DCys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2 60  90 BIM-23255H-DNal-cyclo[Cys-Tyr-DTrp-Lys-Val-DCys]-Thr-NH2 60  91 JF-04-31H-DPhe-cyclo[DCys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2 60  92 DC-13-187H-DPhe-cyclo[DPen-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2 60  93 DC-13-209H-DPhe-cyclo[Cys-Tyr-DTrp-Lys-Val-DPen]-Thr-NH2 60  94 DC-38-19H-Phe-cyclo[DCys-Pal-DTrp-Lys-Thr-Cys]-Thr-NH2 60  95 DC-38-22H-DPhe-cyclo[DCys-Pal-DTrp-Lys-Thr-Cys]-Thr-NH2 60  96 DC-38-15H-Tyr-cyclo[DCys-Pal-DTrp-Lys-Thr-Cys]-Thr-NH2 60  97 DC-38-39H-Nal-cyclo[DCys-Tyr-DTrp-Lys-Val-Cys]-Nal-NH2 60  98 DC-38-35Ac-Nal-cyclo[DCys-Tyr-DTrp-Lys-Val-Cys]-Nal-NH2 60  99 DC-32-57H-DNal-cyclo[DCys-Tyr-DTrp-Lys-Val-Cys]-Nal-NH2 60 100 DC-38-67H-Nal-cyclo[DCys-Tyr-DTrp-Lys-Val-Cys]-DNal-NH2 60 101 DC-38-64H-DNal-cyclo[DCys-Tyr-DTrp-Lys-Val-Cys]-DNal-NH2 60 102 NC-8-61H-DNal-cyclo[DCys-Tyr-DTrp-Lys-Thr-Cys]-Nal-NH2 60 103 DC-32-53H-DNal-cyclo[Cys-Tyr-DTrp-Lys-Val-DCys]-Nal-NH2 60 104 DC-38-70H-Trp-cyclo[DCys-Tyr-DTrp-Lys-Val-Cys]-DNal-NH2 60 105 JF-04-47H-DBip-cyclo[DCys-Tyr-DTrp-Lys-Val-Cys]-Nal-NH2 60 106 RJ-01-14H-Nal-cyclo[DCys-Tyr-DTrp-Lys-Val-Cys]-NHCH(CH3)2 60 107 RJ-01-20H-Nal-cyclo[DCys-His-DTrp-Lys-Val-Cys]-Nal-NH2 60 108 JF-04-27H-Npa-cyclo[DCys-Tyr-DTrp-Lys-Val-Cys]-Tyr-NH2 60 109 DC-38-51H-Phe-cyclo[DCys-Pal-DTrp-Lys-Val-Cys]-Nal-NH2 60 110 RJ-01-28H-Dip-cyclo[DCys-Pal-DTrp-Lys-Val-Cys]-Nal-NH2 60 111 RJ-01-44H-Dip-cyclo[DCys-Pal-DTrp-Lys-Val-Cys]-Nal-NH2 60 112 RJ-01-76H-Dip-cyclo[DCys-Pal-DTrp-Lys-Val-Cys]-Dip-NH2 60 113 RJ-01-31H-Dip-cyclo[DCys-His-DTrp-Lys-Val-Cys]-Dip-NH2 60 114 RJ-01-36H-Dip-cyclo[DCys-HIs-DTrp-Lys-Val-Cys]-Nal-NH2 60 115 RJ-01-40H-Nal-cyclo[DCys-His-DTrp-Lys-Val-Cys]-DDip-NH2 60 116 RJ-01-80H-Nal-cyclo[DCys-Pal-DTrp-Lys-Val-Cys]-Dip-NH2 60 117 DC-37-57H-cyclo[DCys-Phe-Phe-DTrp-Lys-Thr-Phe-Cys]-NH2 60 118 DC-37-83H-cyclo[DCys-Phe-Phe-DTrp-Lys-Thr-Phe-DCys]-NH2 60 119 JF-04-33H-Npa-cyclo[DCys-Pal-DTrp-Lys-Val-Cys]-Tyr-NH2 60 120 DC-41-85H-Fpa-cyclo[Cys-Pal-Trp-Lys-Ile-Lys]-Nal-NH2 63 1213-Pal-cyclo(DCys-3-Pal-DTrp-NMeLys-Thr-Cys)-DTrp-NH2 64 122Cpa-cyclo(DCys-3-Pal-DTrp-Lys-NMe-Thr-Cys)-2-Nal-NH2 64 123Cpa-cyclo(DCys-3-Pal-DTrp-Lys-Thr-Cys)-Nme2-Nal-NH2 64 124Cpa-cyclo(DCys-3-Pal-DTrp-Lys-Thr-NMeCys)-2-Nal-NH2 64 125Cpa-cyclo(DCys-3-Pal-DTrp-NMeLys-Thr-Cys)-2-Nal-NH2 64 126Cpa-cyclo(DCys-3-Pal-DTrp-NMeLys-Thr-Cys)-DTrp-NH2 64 127Cpa-cyclo(DCys-3-Pal-NMeDTrp-Lys-Thr-Cys)-2-Nal-NH2 64 128Cpa-cyclo(DCys-3-Pal-NMeDTrp-NMeLys-Thr-Cys)-2-Nal-NH2 64 129Cpa-cyclo(DCys-NMe3-Pal-DTrp-Lys-Thr-Cys)-2-Nal-NH2 64 130Cpa-cyclo(DCys-Tyr-DTrp-NMeLys-Thr-Cys)-2-Nal-NH2 64 131Cpa-cyclo(NMeDCys-3-Pal-DTrp-Lys-Thr-Cys)-2-Nal-NHMe 64 132Cpa-cyclo(NMeDCys-3-Pal-DTrp-Lys-Thr-Cys)-Dip-NHMe 64 133Nal-cyclo(DCys-3-Pal-DTrp-NMeLys-Thr-Cys)-DTrp-NH2 64 134Nal-cyclo(DCys-Pal-DTrp-NMeLys-Thr-Cys)-DTrp-NH2 64 135NmeCpa-cyclo(DCys-3-Pal-DTrp-Lys-Thr-Cys)-2-Nal-NH2 64 136Tim-cyclo(DCys-3-Pal-DTrp-NMeLys-Thr-Cys)-2-Nal-NH2 64 137H2-DPhe-DPen-Try-DTrp-Lys-Val-Cys-Thr-NH2 65 138H2-Dβ-Nal-DCys-Try-DTry-Lys-Val-Cys-Thr-NH2 65 139H2-DPhe-DCys-Pal-DTrp-Lys-Thr-Cys-Thr-NH2 65 140H2-DPhe-DCys-Tyr-DTrp-Lys-Abu-Cys-Thr-NH2 65 141H2-Dβ-Nal-DCys-Tyr-DTrp-Lys-Abu-Cys-Thr-NH2 65 142H2-Dβ-Nal-DCys-Tyr-DTrp-Lys-Val-Cys-Dβ-Nal-NH2 65 143H2-DP-F-Phe-DCys-Pal-DTrp-Lys-Val-Cys-DP-Fphe-NH2 65 144H2-DBip-DCys-Tyr-DTrp-Lys-Val-Cys-β-Nal-NH2 65 145H2-DDip-DCys-Pal-DTrp-Lys-Val-Cys-β-Nal-NH2 65 146H2-DP-F-Phe-DCys-Pal-DTrp-Lys-Tle-Cys-β-Nal-NH2 65 147H2-Dp-Cl-Phe-DCys-Pal-DTrp-Lys-Tle-Cys-p-Cl-Phe-NH2 65 148p-NO2-DPhe-DCys-Pal-DTrp-Lys-Thr(Bzl)-Cys-Tyr(Bzl)-NH2 65 149p-NO2-DPhe-DCys-Tyr(Bzl)-DTrp-Lys-Val-Cys-Tyr(Bzl)-NH2 65 150 (H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)-p-NO2-DPhe- 65DCys-Pal-DTrp-Lys-Thr(Bzl)-Cys-Tyr(Bzl)-NH2 151 (H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)-p-NO2-DPhe- 65DCys-Tyr(Bzl)-DTrp-Lys-Val-Cys-Tyr(Bzl)-NH2 152 H)(3-phenylpropionyl)-DCys-Tyr-DTrp-Lys-Val-Cys-β-Nal-NH2 66 153 (H)(3-phenylpropionyl)-DCys-Pal-DTrp-Lys-Val-Cys-β-Nal-NH2 66 154 (H)(3-phenylpropionyl)-DCys-Tyr-DTrp-Lys-Thr-Cys-β-Nal-NH2 66 155 (H)(3-phenylpropionyl)-DCys-Pal-DTrp-Lys-Thr-Cys-β-Nal-NH2 66 156 (H)(3-phenylpropionyl)-DCys-Tyr-DTrp-Lys-Val-Cys-Thr-NH2 66 157 (H)(3-phenylpropionyl)-DCys-Pal-DTrp-Lys-Val-Cys-Thr-NH2 66 158 (H)(3-phenylpropionyl)-DCys-Tyr-DTrp-Lys-Thr-Cys-Thr-NH2 66 159 (H)(3-phenylpropionyl)-DCys-Pal-DTrp-Lys-Thr-Cys-Thr-NH2 66 160 (H)(3-[2-naphthyl]propionyl)-DCys-Tyr-DTrp-Lys-Val-Cys-β- 66 Nal-NH2 161(H) (3-[2-naphthyl]propionyl)-DCys-Tyr-DTrp-Lys-Val-Cys-β- 66 Nal-NH2162 (H) (3-[2-naphthyl]proplonyl)-DCys-Pal-DTrp-Lys-Val-Cys-β- 66Nal-NH2 163 (H) (3-[2-naphthyl]propionyl)-DCys-Tyr-DTrp-Lys-Thr-Cys-β-66 Nal-NH2 164 (H)(3-[2-naphthyl]propionyl)-DCys-Pal-DTrp-Lys-Thr-Cys-β- 66 Nal-NH2 165(H) (3-[2-naphthyl]propionyl)-DCys-Tyr-DTrp-Lys-val-Cys-Thr-NH2 66 166(H) (3-[2-naphthyl]propionyl)-DCys-Pal-DTrp-Lys-Val-Cys-Thr-NH2 66 167(H) (3-[2-naphthyl]propionyl)-DCys-Tyr-DTrp-Lys-Thr-Cys Thr-NH2 66 168(H) (3-[2-naphthyl]propionyl)-DCys-Pal-DTrp-Lys-Thr-Cys Thr-NH2 66 169(H) (3-[p-hydroxyphenyl])-DCys-Tyr-DTrp-Lys-Val-Cys-β-Nal-NH2 66 170 (H)(3-naphthyl]propionyl)-DCys-Tyr-DTrp-Lys-Abu-Cys-β-Nal-NH2 66 171 (H)(3-naphthyl]propionyl)-DCys-Tyr-DTrp-Lys-Abu-Cys-Thr-NH2 66 172 (H)(3-phenylylpropionyl)-DCys-Tyr-DTrp-Lys-Abu-Cys-β-Nal-NH2 66 173 (H)(3-phenylylpropionyl)-DCys-Tyr-DTrp-Lys-Abu-Cys-Thr-NH2 66 174H2-β-Nal-DCys-Tyr-DTrp-Lys-Val-Cys-β-Nal-NH2 (Analog No. 2) 67 175(H)(CH3CO)-β-Nal-DCys-Tyr-DTrp-Lys-Val-Cys-β-Nal-NH2 (Analog No. 5) 67176 (H)-(4-(2-hydroxyethyl)-1-piperazinylacetyl)-β-Nal-DCys-Tyr-DTrp- 67Lys-Val-Cys-β-Nal-NH2 177(H)-(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-β-Nal-DCys-Tyr- 67DTrp-Lys-Val-Cys-β-Nal-NH2 178H2-β-Nal-DCys-Pal-DTrp-Lys-Val-Cys-β-Nal-NH2 (Analog No. 3) 67 179(H)(CH3CO)-β-Nal-DCys-Pal-DTrp-Lys-Val-Cys-β-Nal-NH2 67 180(H)-(4-(2-hydroxyethyl)-1-piperazinylacetyl)-β-Nal-DCys-Pal-DTrp- 67Lys-Val-Cys-β-Nal-NH2 181(H)-(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-β-Nal-DCys-Pal- 67DTrp-Lys-Val-Cys-β-Nal-NH2 182H2-β-Nal-DCys-Tyr-DTrp-Lys-Val-Cys-Thr-NH2 67 183(H)(CH3CO)-β-Nal-DCys-Tyr-DTrp-Lys-Val-Cys-Thr-NH2 67 184(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)-β-Nal-DCys-Tyr-DTrp-Lys- 67Val-Cys-Thr-NH2 185(H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-β-Nal-DCys-Tyr- 67DTrp-Lys-Val-Cys-Thr-NH2 186 H2-β-Nal-DCys-Pal-DTrp-Lys-Val-Cys-Thr-NH267 187 (H)(CH3CO)-β-Nal-DCys-Pal-DTrp-Lys-Val-Cys-Thr-NH2 67 188(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)-β-Nal-DCys-Pal-DTrp-Lys- 67Val-Cys-Thr-NH2 189(H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-β-Nal-DCys-Pal- 67DTrp-Lys-Val-Cys-Thr-NH2 190 H2-Phe-DCys-Tyr-DTrp-Lys-Val-Cys-β-Nal-NH267 191 (H)(CH3CO)Phe-DCys-Tyr-DTrp-Lys-Val-Cys-β-Nal-NH2 67 192(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)-Phe-DCys-Tyr-DTrp-Lys- 67Val-Cys-β-Nal-NH2 193(H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-Phe-DCys-Tyr- 67DTrp-Lys-Val-Cya-β-Nal-NH2 194H2-Phe-DCys-Pal-DTrp-Lys-Val-Cys-β-Nal-NH2 (Analog No. 4) 67 195(H)(CH3CO)Phe-DCys-Pal-DTrp-Lys-Val-Cys-β-Nal-NH2 67 196(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)-Phe-DCys-Pal-DTrp-Lys- 67Val-Cys-β-Nal-NH2 197(H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-Phe-DCys-Pal- 67DTrp-Lys-Val-Cys-β-Nal-NH2 198 H2-Phe-DCys-Pal-DTrp-Lys-Val-Cys-Thr-NH267 199 (H)(CH3CO)-Phe-DCys-Pal-DTrp-Lys-Val-Cys-Thr-NH2 67 200(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)-Phe-DCys-Pal-DTrp-Lys- 67Val-Cys-Thr-NH2 201(H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-Phe-DCys-Pal- 67DTrp-Lys-Val-Cys-Thr-NH2 202H2-β-Nal-DCys-Tyr-DTrp-Lys-Thr-Cys-β-Nal-NH2 67 203(H)(CH3CO)-β-Nal-DCys-Pal-DTrp-Lys-Thr-Cys-β-Nal-NH2 67 204(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)-β-Nal-DCys-Tyr-DTrp-Lys- 67Thr-Cys-β-Nal-NH2 205(H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-β-Nal-DCys-Tyr- 67DTrp-Lys-Thr-Cys-β-Nal-NH2 206H2-β-Nal-DCys-Pal-DTrp-Lys-Thr-Cys-β-Nal-NH2 67 207(H)(CH3CO)-β-Nal-DCys-Pal-DTrp-Lys-Thr-Cys-β-Nal-NH2 67 208(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)-β-Nal-DCys-Pal-DTrp-Lys- 67Thr-Cys-β-Nal-NH2 209(H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-β-Nal-DCys-Pal- 67DTrp-Lys-Thr-Cys-β-Nal-NH2 210H2-β-Nal-DCys-Tyr-DTrp-Lys-Thr-Cys-Thr-NH2 67 211H(CH3CO)-β-Nal-DCys-Tyr-DTrp-Lys-Thr-Cys-Thr-NH2 67 212(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)-β-Nal-DCys-Tyr-DTrp-Lys- 67Thr-Cys-Thr-NH2 213(H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-β-Nal-DCys-Tyr- 67DTrp-Lys-Thr-Cys-Thr-NH2 214 H2-β-Nal-DCys-Pal-DTrp-Lys-Thr-Cys-Thr-NH267 215 (H)(CH3CO)-β-Nal-DCys-Pal-DTrp-Lys-Thr-Cys-Thr-NH2 67 216(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)-β-Nal-DCys-Pal-DTrp-Lys- 67Thr-Cys-Thr-NH2 217(H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-β-Nal-DCys-Pal- 67DTrp-Lys-Thr-Cys-Thr-NH2 218 H2-Phe-DCys-Tyr-DTrp-Lys-Thr-Cys-β-Nal-NH267 219 (H)(CH3CO)Phe-DCys-Tyr-DTrp-Lys-Thr-Cys-β-Nal-NH2 67 220(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)Phe-DCys-Tyr-DTrp-Lys- 67Thr-Cys-β-Nal-NH2 221(H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)Phe-DCys-Tyr- 67DTrp-Lys-Thr-Cys-β-Nal-NH2 222H2-Phe-DCys-Pal-DTrp-Lys-Thr-Cys-β-Nal-NH2 67 223(H)(CH3CO)Phe-DCys-Pal-DTrp-Lys-Thr-Cys-β-Nal-NH2 67 224(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)Phe-DCys-Pal-DTrp-Lys- 67Thr-Cys-β-Nal-NH2 225(H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)Phe-DCys-Pal- 67DTrp-Lys-Thr-Cys-β-Nal-NH2 226 H2-Phe-DCys-Tyr-DTrp-Lys-Thr-Cys-Thr-NH267 227 (H)(CH3CO)Phe-DCys-Tyr-DTrp-Lys-Thr-Cys-Thr-NH2 67 228(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)Phe-DCys-Tyr-DTrp-Lys- 67Thr-Cys-Thr-H2 229(H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-Phe-DCys-Tyr- 67DTrp-Lys-Thr-Cys-Thr-NH2 230 H2-Phe-DCys-Pal-DTrp-Lys-Thr-Cys-Thr-NH2(Analog No. 6) 67 231 (H)(CH3CO)-Phe-DCys-Pal-DTrp-Lys-Thr-Cys-Thr-NH267 232 (H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)Phe-DCys-Pal-DTrp-Lys-67 Thr-Cys-Thr-NH2 233(H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)Phe-DCys-Pal- 67DTrp-Lys-Thr-Cys-Thr-NH2 234H2-β-Nal-DCys-Tyr-DTrp-Lys-Abu-Cys-β-Nal-NH2 67 235H2-Phe-DCys-Tyr-DTrp-Lys-Abu-Cys-β-Nal-NH2 67 236H2-β-Nal-DCys-Pal-DTrp-Lys-Abu-Cys-β-Nal-NH2 67 237H2-Phe-DCys-Pal-DTrp-Lys-Abu-Cys-β-Nal-NH2 67 238H2-β-Nal-DCys-Tyr-DTrp-Lys-Abu-Cys-Thr-NH2 67 239H2-Phe-DPen-Tyr-DTrp-Lys-Val-Pen-β-Nal-NH2 67 240H2-Phe-DPen-Pal-DTrp-Lys-Thr-Pen-Thr-NH2 67 241H2-Dip-DCys-Pal-DTrp-Lys-Val-Cys-Dip-NH2 (Analog No. 10) 67 242H2-F5-Phe-DCys-His-DTrp-Lys-Val-Cys-F6-Phe-NH2 (Analog No. 11) 67 243H2-Dip-DCys-Pal-DTrp-Lys-Val-Cys-β-Nal-NH2 (Analog No. 13) 67 244H2-m-F-Phe-DCys-Pal-DTrp-Lys-Val-Cys-m-F-Phe-NH2 (Analog No. 14) 67 245H2-o-F-Phe-DCys-Pal-DTrp-Lys-Val-Cys-o-F-Phe-NH2 (Analog No. 15) 67 246H2-p-F-Phe-DCys-Pal-DTrp-Lys-Val-Cys-p-F-Phe-NH2 (Analog No. 12) 67 247H2-F5-Phe-DCys-Pal-DTrp-Lys-Val-Cys-F5-Phe-NH2 (Analog No. 16) 67 248H2-F5-Phe-DCys-2-Pal-DTrp-Lys-Val-Cys-F5-Phe-NH2 (Analog No. 17) 67 249H2-β-Nal-DCys-His-DTrp-Lys-Val-Cys-DDip-NH2 (Analog No. 19) 67 250H2-Dip-DCys-His-DTrp-Lys-Val-Cys-β-Nal-NH2 (Analog No. 20) 67 251H2-Dip-DCys-His-DTrp-Lys-Val-Cys-Dip-NH2 (Analog No. 21) 67 252 is5H2-β-Nal-DCys-His-DTrp-Lys-Val-Cys-β-Nal-NH2 (Analog No. 22) 67 253H2-Trp-DCys-Tyr-DTrp-Lys-Val-Cys-Dβ-Nal-NH2 (Analog No. 24) 67 254H2-β-Nal-DCys-Tyr-DTrp-Lys-Val-Cys-Dβ-Nal-NH2 (Analog No. 25) 67 255H2-β-Nal-DCys-Pal-DTrp-Lys-Val-Cys-Dp-F-Phe-NH2 (Analog No. 28) 67 256H2-β-Nal-DCys-Pal-DTrp-Lys-Tle-Cys-β-Nal-NH2 (Analog No. 29) 67 257H2-p-F-Phe-DCys-Pal-DTrp-Lys-Val-Cys-β-Nal-NH2 (Analog No. 30) 67 258H2-β-Nal-DCys-Pal-DTrp-Lys-Nle-Cys-β-Nal-NH2 (Analog No. 31) 67 259H2-β-Nal-DCys-Pal-DTrp-Lys-Ile-Cys-β-Nal-NH2 (Analog No. 32) 67 260H2-β-Nal-DCys-Pal-DTrp-Lys-Gly-Cys-β-Nal-NH2 (Analog No. 33) 67 261H2-β-Nal-DCys-Pal-DTrp-Lys-Ala-Cys-β-Nal-NH2 (Analog No. 34) 67 262H2-β-Nal-DCys-Pal-DTrp-Lys-Leu-Cys-β-Nal-NH2 (Analog No. 35) 67 263H2-Bip-DCys-Tyr-DTrp-Lys-Ile-Cys-Bip-NH2 (Analog No. 36) 67 264H2-p-F-Phe-DCys-His-DTrp-Lys-Val-Cys-p-F-Phe-NH2 (Analog No. 38) 67 265H2-Npa-DCys-Pal-DTrp-Lys-Val-Cys-Tyr-NH2 (Analog No. 39) 67 266H2-m-F-Phe-DCys-His-DTrp-Lys-Val-Cys-m-F-Phe-NH2 (Analog No. 40) 67 267H2-o-F-Phe-DCys-His-DTrp-Lys-Val-Cys-o-F-Phe-NH2 (Analog No. 41) 67 268H2-β-Nal-DCys-Pal-DTrp-Lys-Val-Cys-Dip-NH2 (Analog No. 42) 67 269H2-Cpa-DCys-Pal-DTrp-Lys-Val-Cys-Cpa-NH2 (Analog No. 43) 67 270H2-Igl-DCys-Pal-DTrp-Lys-Val-Cys-Igl-NH2 (Analog No. 44) 67 271H2-β-Nal-DCys-Pal-DTrp-Lys-Val-Cys-DDip-NH2 (Analog No. 45) 67 272H2-β-Nal-DCys-3-l-Tyr-DTrp-Lys-Val-Cys-β-Nal-NH2 (Analog No. 46) 67 273H2-p-CN-Phe-DCys-Pal-DTrp-Lys-Val-Cys-p-CN-Phe-NH (Analog No. 47) 67 274H2-β-Nal-DCys-Tyr-DTrp-Lys-Val-Cys-DDip-NH2 (Analog No. 48) 67 275H2-β-Nal-DCys-Bta-DTrp-Lys-Val-Cys-β-Nal-NH2 (Analog No. 49) 67 276H2-p-F-Phe-DCys-Pal-DTrp-Lys-Tle-Cys-β-Nal-NH2 (Analog No. 50) 67 277H2-Bpa-DCys-Pal-DTrp-Lys-Val-Cys-Bpa-NH2 (Analog No. 52) 67 278H2-Iph-DCys-Pal-DTrp-Lys-Val-Cys-Iph-NH2 (Analog No. 53) 67 279H2-Trp-DCys-Pal-DTrp-Lys-Tle-Cys-β-Nal-NH2 (Analog No. 54) 67 280H2-p-Cl-Phe-DCys-Pal-DTrp-Lys-Val-Cys-β-Nal-NH2 (Analog No. 55) 67 281H2-p-Cl-Phe-DCys-Pal-DTrp-Lys-Tle-Cys-β-Nal-NH2 (Analog No. 56) 67 282H2-p-Cl-Phe-DCys-Pal-DTrp-Lys-Tle-Cys-p-Cl-Phe-NH2 (Analog No. 57) 67283 H2-p-Cl-Phe-DCys-Pal-DTrp-Lys-Cha-Cys-p-Cl-Phe-NH2 67 284H2-p-Cl-Phe-DCys-Tyr(I)-DTrp-Lys-Val-Cys-p-Cl-Phe-NH2 67 285H2-p-Cl-Phe-DCys-Tyr(I)-DTrp-Lys-Val-Cys-β-Nal-NH2 67 286H2-p-Cl-Phe-DCys-Tyr(I)-DTrp-Lys-Tle-Cys-β-Nal-NH2 67 287H2-p-F-Phe-DCys-Tyr(I)-DTrp-Lys-Val-Cys-β-Nal-NH2 67 288H2-p-F-Phe-DCys-Tyr(I)-DTrp-Lys-Tle-Cys-β-Nal-NH2 67 289H2-β-Nal-DCys-Tyr-DTrp-Lys-Abu-Cys-β-Nal-NH2 67 290(H)(CH3CO)-β-Nal-DCys-Tyr-DTrp-Lys-Abu-Cys-β-Nal-NH2 67 291H2-p-NO2-Phe-DCys-Tyr-DTrp-Lys-Abu-Cys-β-Nal-NH2 67 292(H)(CH3CO)-p-NO2-Phe-DCys-Tyr-DTrp-Lys-Abu-Cys-β-Nal-NH2 67 293H2-p-NO2-Phe-DCys-Tyr(Bzl)-DTrp-Lys-Thr(Bzl)Cys-β-Nal-NH2 67 294(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)-p-NO2-Phe-DCys- 67Tyr(Bzl)-DTrp-Lys-Thr(Bzl)-Cys-β-Nal-NH2 295(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)-p-NO2-Phe-DCys-Tyr- 67DTrp-Lys-Thr-Cys-Thr-NH2 296H2-p-NO2-Phe-DCys-Tyr-DTrp-Lys-Val-Cys-β-Nal-NH2 67 297(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)-p-NO2-Phe-DCys-Tyr- 67DTrp-Lys-Val-Cys-β-Nal-NH2 298(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)-β-Nal-Phe-DCys-Tyr- 67DTrp-Lys-Val-Cys-β-Nal-NH2 299H2-β-Nal-DCys-Tyr(Bzl)-DTrp-Lys-Thr(Bzl)-Cys-β-Nal-NH2 67 300(H)(4-2-hydroxyethyl)-1-piperazinylacetyl)-β-Nal-DCys-Tyr(Bzl)- 67DTrp-Lys-Thr(Bzl)-Cys-Tyr(Bzl)-NH2 301H2-DPhe-DPen-Tyr-DTrp-Lys-Val-Cys-Thr-NH2 67 302H2-Dβ-Nal-DCys-Tyr-DTrp-Lys-Val-Cys-Thr-NH2 67 303H2-Dβ-Nal-DCys-Tyr-DTrp-Lys-Val-Cys-β-Nal-NH2 (Analog No. 9) 67 304H2-Dβ-Nal-DCys-Tyr-DTrp-Lys-Thr-Cys-β-Nal-NH2 67 305H2-DPhe-DCys-Pal-DTrp-Lys-Thr-Cys-Thr-NH2 67 306H2-DPhe-DCys-Tyr-DTrp-Lys-Abu-Cys-Thr-NH2 67 307H2-Dβ-Nal-DCys-Tyr-DTrp-Lys-Abu-Cys-Thr-NH2 67 308H2-Dβ-Nal-DCys-Tyr-DTrp-Lys-Val-Cys-Dβ-Nal-NH2 (Analog No. 26) 67 309H2-Dp-F-Phe-DCys-Pal-DTrp-Lys-Val-Cys-Dp-F-Phe-NH2 (Analog No. 27) 67310 H2-DBip-DCys-Tyr-DTrp-Lys-Val-Cys-β-Nal-NH2 (Analog No. 37) 67 311H2-DDip-DCys-Pal-DTrp-Lys-Val-Cys-β-Nal-NH2 (Analog No. 18) 67 312H2-DP-F-Phe-DCys-Pal-DTrp-Lys-Tle-Cys-β-Nal-NH2 (Analog No. 51) 67 313H2-Dp-Cl-Phe-DCys-Pal-DTrp-Lys-Tle-Cys-p-Cl-Phe-NH2 (Analog No. 7) 67314 p-NO2-DPhe-DCys-Pal-DTrp-Lys-Thr(Bzl)-Cys-Tyr(Bzl)-NO2 67 315p-NO2-DPhe-DCys-Tyr(Bzl)-DTrp-Lys-Val-Cys-Tyr(Bzl)-NH2 67 316(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)-p-NO2-DPhe-DCys-Pal- 67DTrp-Lys-Thr(Bzl)-Cys-Tyr(Bzl)-NH2 317(H)C4-(2-hydroxyethyl)-1-piperazinylacetyl)-p-NO2-DPhe-DCys- 67Tyr(Bzl)-DTrp-Lys-Val-Cys-Tyr(Bzl)-NH2 318(H)(3-phenylpropionyl)-DCys-Tyr-DTrp-Lys-Val-Cys-β-Nal-NH2 67 319(H)(3-phenylpropionyl)-DCys-Pal-DTrp-Lys-Val-Cys-β-Nal-NH2 67 320(H)(3-phenylpropionyl)-DCys-Tyr-DTrp-Lys-Thr-Cys-β-Nal-NH2 67 321(H)(3-phenylpropionyl)-DCys-Pal-DTrp-Lys-Thr-Cys-β-Nal-NH2 67 322(H)(3-phenylpropionyl)-DCys-Tyr-DTrp-Lys-Val-Cys-Thr-NH2 67 323(H)(3-phenylpropionyl)-DCys-Pal-DTrp-Lys-Val-Cys-Thr-NH2 67 324(H)(3-phenylpropionyl)-DCys-Tyr-DTrp-Lys-Thr-Cys-Thr-NH2 67 325(H)(3-phenylpropionyl)-DCys-Pal-DTrp-Lys-Thr-Cys-Thr-NH2 67 326(H)(3-[2-naphthyl]propionyl)-DCys-Tyr-DTrp-Lys-Val-Cys-β-Nal-NH2 67 327(H)(3-[2-naphthyl]propionyl)-DCys-Pal-DTrp-Lys-Val-Cys-β-Nal-NH2 67 328(H)(3-[2-naphthyl]propionyl)-DCys-Tyr-DTrp-Lys-Thr-Cys-β-Nal-NH2 67 329(H)(3-[2-naphthyl]propionyl)-DCys-Pal-DTrp-Lys-ahr-Cys-β-Nal-NH2 67 330(H)(3-[2-naphthyl]propionyl)-DCys-Tyr-DTrp-Lys-Val-Cys-Thr-NH2 67 331(H)(3-[2-naphthyl]propionyl)-DCys-Pal-DTrp-Lys-Val-Cys-Thr-NH2 67 332(H)(3-[2-naphthyl]propionyl)-DCys-Tyr-DTrp-Lys-Thr-Cys-Thr-NH2 67 333(H)(3-[2-naphthyl]propionyl)-DCys-Pal-DTrp-Lys-Thr-Cys-Thr-NH2 67 334(H)(3-[p-hydroxyphenyl])-DCys-Tyr-DTrp-Lys-Val-Cys-β-Nal-NH2 67 335(H)(3-naphthyl]propionyl)-DCys-Tyr-DTrp-Lys-Abu-Cys-β-Nal-NH2 67 336(H)(3-naphthyl]propionyl)-DCys-Tyr-DTrp-Lys-Abu-Cys-Thr-NH2 67 337(H)(3-phenylylpropionyl)-DCys-Tyr-DTrp-Lys-Abu-Cys-β-Nal-NH2 67 338(H)(3-phenylylpropionyl)-DCys-Tyr-DTrp-Lys-Abu-Cys-Thr-NH2 67 339H2-β-Nal-DCys-Tyr-DTrp-Lys-Val-Cys-2R,3R-(2-hydroxymethyl)-3- 67hydroxy)propylamide 340(H)(CH3CO)-β-Nal-DCys-Tyr-DTrp-Lys-Val-Cys-2R,3R-(2- 67hydroxymethyl)-3-hydroxy)propylamide 341(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)-β-Nal-DCys-Tyr-DTrp-Lys- 67Val-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide 342(H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-β-Nal-DCys-Tyr- 67DTrp-Lys-Val-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide 343H2-β-Nal-DCys-Pal-DTrp-Lys-Val-Cys-2R,3R-(2-hydroxymethyl)-3- 67hydroxy)propylamide 344(H)(CH3CO)-β-Nal-DCys-Pal-DTrp-Lys-Val-Cys-2R,3R-(2-hydroxymethyl)- 673-hydroxy)propylamide 345(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)-β-Nal-DCys-Pal-DTrp-Lys- 67Val-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide 346(H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-β-Nal-DCys-Pal- 67DTrp-Lys-Val-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide 347H2-β-Nal-DCys-Tyr-DTrp-Lys-Thr-Cys-2R,3R-(2-hydroxymethyl)-3- 67hydroxy)propylamide 348(H)(CH3CO)-β-Nal-DCys-Tyr-DTrp-Lys-Thr-Cys-2R,3R-(2-hydroxymethyl)- 673-hydroxy)propylamide 349(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)-β-Nal-DCys-Tyr-DTrp-Lys- 67Thr-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide 350(H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-β-Nal-DCys-Tyr- 67DTrp-Lys-Thr-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide 351H2-Nal-DCys-Pal-DTrp-Lys-Thr-Cys-2R,3R-(2-hydroxymethyl)-3- 67hydroxy)propylamide 352(H)(CH3CO)-β-Nal-DCys-Pal-DTrp-Lys-Thr-Cys-2R,3R-(2-hydroxymethyl)- 673-hydroxy)propylamide 353(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)-β-Nal-DCys-Pal-DTrp-Lys- 67Thr-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide 354(H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-β-Nal-DCys-Pal- 67DTrp-Lys-Thr-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide 355H2-Phe-DCys-Tyr-DTrp-Lys-Val-Cys-2R,3R-(2-hydroxymethyl)-3- 67hydroxy)propylamide 356(H)(CH3CO)Phe-DCys-Tyr-DTrp-Lys-Val-Cys-2R,3R-(2-hydroxymethyl)- 673-hydroxy)propylamide 357(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)Phe-DCys-Tyr-DTrp-Lys- 67Val-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide 358(H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)Phe-DCys-Tyr- 67DTrp-Lys-Val-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide 359H2-Phe-DCys-Pal-DTrp-Lys-Val-Cys-2R,3R-(2-hydroxymethyl)-3- 67hydroxy)propylamide 360H(CH3CO)Phe-DCys-Pal-DTrp-Lys-Val-Cys-2R,3R-(2-hydroxymethyl)- 673-hydroxy)propylamide 361(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)Phe-DCys-Pal-DTrp-Lys- 67Val-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide 362(H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)Phe-DCys-Pal- 67DTrp-Lys-Val-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide 363H2-Phe-DCys-Tyr-DTrp-Lys-Thr-Cys-2R,3R-(2-hydroxymethyl)-3- 67hydroxy)propylamide 364(H)(CH3CO)Phe-DCys-Tyr-DTrp-Lys-Thr-Cys-2R,3R-(2-hydroxymethyl)- 673-hydroxy)propylamide 365(H)C4-(2-hydroxyethyl)-1-piperazinylacetyl)Phe-DCys-Tyr-DTrp-Lys- 67Thr-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide 366(H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)Phe-DCys-Tyr- 67DTrp-Lys-Thr-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)proplylamide 367H2-Phe-DCys-Pal-DTrp-Lys-Thr-Cys-2R,3R-(2-hydroxymethyl)-3- 67hydroxy)propylamide 368(H)(CH3CO)Phe-DCys-Pal-DTrp-Lys-Thr-Cys-2R,3R-(2-hydroxymethyl)- 67hydroxymethyl)-3-hydroxy)propylamide 369(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)Phe-DCys-Pal-DTrp-Lys- 67Thr-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide 370(H)4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)Phe-DCys-Pal- 67DTrp-Lys-Thr-Cys-2R,3R-(2-hydroxymethyl)-3-hydroxy)propylamide 371H2-β-Nal-DCys-Tyr-DTrp-Lys-Val-Cys-2R-(2-naphthyl)ethylamide 67 372(H)(CH3CO)-β-Nal-DCys-Tyr-DTrp-Lys-ValCys-2R-(2-naphthyl)ethylamide 67373 (H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)-β-Nal-DCys-Tyr-DTrp-Lys-67 Val-Cys-2R-(2-naphthyl)ethylamide 374(H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-β-Nal-DCys-Tyr- 67DTrp-Lys-Val-Cys-2R-(2-naphthyl)ethylamide 375H2-β-Nal-DCys-Pal-DTrp-Lys-Val-Cys-2R-(2-naphthyl)ethylamide 67 376(H)(CH3CO)-β-Nal-DCys-Pal-DTrp-Lys-Val-Cys-2R-(2-naphthyl)ethylamide 67377 (H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)-β-Nal-DCys-Pal-DTrp-Lys-67 Val-Cys-2R-(2-naphthyl)ethylamide 378(H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-β-Nal-DCys-Pal- 67DTrp-Lys-Val-Cys-2R-(2-naphthyl)ethylamide 379H2-β-Nal-DCys-Tyr-DTrp-Lys-Thr-Cys-2R-(2-naphthyl)ethyl amide 67 380(H)(CH2CO)-β-Nal-DCys-Tyr-DTrp-Lys-Thr-Cys-2R-(2-naphthyl)ethylamide 67381 (H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)-β-Nal-DCys-Tyr-DTrp-Lys-67 Thr-Cys-2R-(2-naphthyl)ethylamide 382(H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-β-Nal-DCys-Tyr- 67DTrp-Lys-Thr-Cys-2R-(2-naphthyl)ethylamide 383H2-β-Nal-DCys-Pal-DTrp-Lys-Thr-Cys-2R-(2-naphthyl)ethylamide 67 384(H)(CH3CO)-β-Nal-DCys-Pal-DTrp-Lys-Thr-Cys-2R-(2-naphthyl)ethylamide 67385 (H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)-β-Nal-DCys-Pal-DTrp-Lys-67 Thr-Cys-2R-(2-naphthyl)ethylamide 386(H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-β-Nal-DCys-Pal- 67DTrp-Lys-Thr-Cys-2R-(2-naphthyl)ethylamide 387H2-Phe-DCys-Tyr-DTrp-Lys-Val-Cys-2R-(2-naphthyl)ethylamide 67 388(H)(CH3CO)Phe-DCys-Tyr-DTrp-Lys-Val-Cys-2R-(2-naphthyl)ethylamide 67 389(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)Phe-DCys-Tyr-DTrp-Lys- 67Val-Cys-2R-(2-naphthyl)ethylamide 390(H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)Phe-DCys-Tyr- 67DTrp-Lys-Val-Cys-2R-(2-naphthyl)ethylamide 391H2-Phe-DCys-Pal-DTrp-Lys-Val-Cys-2R-(2-naphthyl)ethylamide 67 392(H)(CH3CO)Phe-Cys-Pal-DTrp-Lys-Val-Cys-2R-(2-naphthyl)ethylamide 67 393(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)Phe-DCys-Pal-DTrp-Lys- 67Val-Cys-2R-(2-naphthyl)ethylamide 394(H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)Phe-DCys-Pal- 67DTrp-Lys-Val-Cys-2R-(2-naphthyl)ethylamide 395H2-Phe-DCys-Tyr-DTrp-Lys-Thr-Cys-2R-(2-naphthyl)ethylamide 67 396(H)(CH3CO)Phe-DCys-Tyr-DTrp-Lys-Thr-Cys-2R-(2-naphthyl)ethylamide 67 397(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)Phe-DCys-Tyr-DTrp-Lys- 67Thr-Cys-2R-(2-naphthyl)ethylamide 398(H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)Phe-DCys-Tyr- 67DTrp-Lys-Thr-Cys-2R-(2-naphthyl)ethylamide 399H2-Phe-DCys-Pal-DTrp-Lys-Thr-Cys-2R-(2-naphthyl)ethylamide 67 400(H)(CH3CO)Phe-DCys-Pal-DTrp-Lys-Thr-Cys-2R-(2-naphthyl)ethylamide 67 401(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)Phe-DCys-Pal-DTrp-Lys- 67Thr-Cys-2R-(2-naphthyl)ethylamide 402(H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)Phe-DCys-Pal- 67DTrp-Lys-Thr-Cys-2R-(2-naphthyl)ethylamide 403H2-β-Nal-DCys-Tyr-DTrp-Lys-Abu-Cys-2R-(2-naphthyl)ethylamide 67 404H2-Phe-DCys-Tyr-DTrp-Lys-Abu-Cys-2R-(2-naphthyl)ethylamide 67 405H2-β-Nal-DCys-Tyr-DTrp-Lys-Abu-Cys-2R,3R-(2-hydroxymethyl)-3- 67hydroxy)propylamide 406H2-Phe-DCys-Tyr-DTrp-Lys-Abu-Cys-2R,3R-(2-hydroxymethyl)-3- 67hydroxy)propylamide 407 H2-Phe-DPhe-Tyr-DTrp-Lys-Thr-Phe-Thr-NH2 67 408H2-Phe-DPhe-Tyr-DTrp-Lys-Val-Phe-Thr-NH2 67 409H2-Phe-DCpa-Tyr-DTrp-Lys-Val-Phe-Thr-NH2 67 410H2-β-Nal-DCpa-Tyr-DTrp-Lys-Val-Phe-Thr-NH2 (Analog No. 1) 67 411(H)(CH3CO)-β-Nal-DCpa-Tyr-DTrp-Lys-Val-Phe-Thr-NH2 67 412(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)-β-Nal-DCpa-Tyr-DTrp- 67Lys-Val-Phe-Thr-NH2 413(H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-β-Nal-DCpa-Tyr- 67DTrp-Lys-Val-Phe-Thr-NH2 414 H2-β-Nal-DCpa-Pal-DTrp-Lys-Val-Phe-Thr-NH267 415 (H)(CH3CO)-β-Nal-DCpa-Pal-DTrp-Lys-Val-Phe-Thr-NH2 67 416(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)-β-Nal-DCpa-Pal-DTrp- 67Lys-Val-Phe-Thr-NH2 417(H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-β-Nal-DCpa-Pal- 67DTrp-Lys-Val-Phe-Thr-NH2 418 H2-β-Nal-DCpa-Tyr-DTrp-Lys-Thr-Phe-Thr-NH267 419 (H)(CH3CO)-β-Nal-DCpa-Tyr-DTrp-Lys-Thr-Phe-Thr-NH2 67 420(H)(4-(2-hydroxyethyl)-1-piperazlnylacetyl)-β-Nal-DCpa-Tyr-DTrp- 67Lys-Thr-Phe-Thr-NH2 421(H)(4-(2-hydroxyethyl)-1-piperizineethanosulfonyl)-β-Nal-DCpa-Tyr- 67DTrp-Lys-Thr-Phe-Thr-NH2 422 H2-β-Nal-DCpa-Pal-DTrp-Lys-Thr-Phe-Thr-NH267 423 (H)(CH3CO)-β-Nal-DCpa-Pal-DTrp-Lys-Thr-Phe-Thr-NH2 67 424(H)(4-(2-hydroxyelhyl)-1-piperazinylacetyl)-β-Nal-DCpa-Pal-DTrp- 67Lys-Thr-Phe-Thr-NH2 425(H)(4-(2-hydroxyethyl)-1-piperlzineethanesulfonyl)-β-Nal-DCpa-Pal- 67DTrp-Lys-Thr-Phe-Thr-NH2 426H2-β-Nal-DCpa-Tyr-DTrp-Lys-Val-Phe-β-Nal-NH2 67 427(H)(CH3CO)-β-Nal-DCpa-Tyr-DTrp-Lys-Val-Phe-β-Na-NH2 67 428(H)(4-(2-hydroxyethyl)-1-piperazinylacetyl)-β-Nal-DCpa-Tyr-DTrp- 67Lys-Val-Phe-β-Nal-NH2 429(H)(4-(2-hydroxyethyl)-1-piperizineethanesulfonyl)-β-Nal-DCpa-Tyr- 67DTrp-Lys-Val-Phe-β-Nal-NH2 430H2-β-Nal-DCpa-Tyr-DTrp-Lys-Val-Phe-β-Nal-NH2 (Analog No. 23) 67 431H2-β-Nal-DCpa-Tyr-DTrp-Lys-Val-Phe-Thr-NH2 67 432H2-Dβ-Nal-DCpa-Phe-DTrp-Lys-Val-Phe-Thr-NH2 67 433H2-Dβ-Nal-DPhe-Tyr-DTrp-Lys-Thr-Phe-Thr-NH2 67 434H2-DPhe-DPhe-Tyr-DTrp-Lys-Val-Phe-Thr-NH2 67 435H2-Dβ-Nal-DCpa-Tyr-DTrp-Lys-Val-Phe-Thr-NH2 (Analog No. 8) 67 436H2-Dβ-Nal-DCpa-Tyr-DTrp-Lys-Val-Phe-β-Nal-NH2 67 * or a pharmaceuticallyaccepted salt thereof.

TABLE 7 Subset of SSTR Peptide Antagonists* Affinity Action ReceptorLigand Name (nM) Units References Antagonist SSTR-2 AC-178, 335  6.8pKi7 49, 81, 82 Antagonist SSTR-2 BIM 23, 458 27.4 plC50 27, 28, 51, 54,55, 56 Antagonist SSTR-2 BIM 23, 627  6.4 plC50 49, 52, 56 AntagonistSSTR-2 BIM 23, 454 31.6 plC50 49, 57, 59 Antagonist SSTR-2 D-Tyr8-CYN 8.4-8.9 pKi81 49, 57, 59 154806 Antagonist SSTR-2 L-Tyr8-CYN  8.1-8.4pKi81 53, 60 154806 Antagonist SSTR-2 PRL-2915  7.9 pKi52 49, 53, 60Antagonist SSTR-2 PRL-2970  7.8 pKi52 51, 56, 61, 62 Seq. ID ActionStructure No. Antagonist AC-His-Phe-Ile-Arg-Trp-Phe-NH2 27 AntagonistH-Fpa-cyclo[DCys-Pal-DTrp-Lys-Tle-Cys]-Nal-NH2 28 AntagonistH-p-Chloro-DPhe-cyclo[DCys-Pal-Trp-Lys-Val-Cys]-2-Nal-NH2 29 AntagonistH-Cpa-Cys-Pal-Trp-Lys-Val-Cys-Nal-NH2 30 AntagonistAc-4-NO2-Phe-cyclo[D-Cys-Tyr-DTrp-Lys-Thr-Cys]-DTyr-NH2 31 AntagonistAc-4-NO2-Phe-cyclo[DCys-Tyr-DTrp-Lys-Thr-Cys]-LTyr-NH2 32 AntagonistH-Cpa-cyclo[DCys-Pal-DTrp-Lys-Tle-Cys]-Nal-NH2 33 AntagonistH-Cpa-cyclo[DCys-Tyr-DTrp-Lys-thr-Cys]-Nal-NH2 34 *and pharmaceuticallyaccepted salts thereof.

TABLE 8 List of Abbreviations* Used 2,4-dichloro-Pheβ-[2,4-dichlorophenyl]-alanine 1-Nal 3-(1-naphthyl)alanine 2Fpa2-fluorophenylalanine 2-Nal 3-(2-naphthyl)alanine 2Pal 2-pyridylalanine2-Pal [2-pyridyl]-alanine or 3-(2-pyridyl)alanine 3Fpa3-fluorophenylalanine 3-I-Tyr 3-iodotyrosine 3-Pal 3-(3-pyridyl)alanine4-Pal 3-(4-pyridyl)alanine Abu 2-aminobutyric acid or α-aminobutyricacid Ahp 7-aminoheptanoic acid Aib 2-aminoisobutyric acid orα-aminoisobutyric acid Amp 4-amino-phenylalanine Ava 5-aminovaleric acidβ-Ala β-alanine or 3-aminopropionic acid β-1-Nal β-[1-naphthyl]-alanineβ-Nal β-[2-napthyl]-alanine Bip biphenylalanine or 4,4′-biphenylalanineBpa 4-bromophenylalanine Bta benzothienylalanine or3-benzothienylalanine Cha cyclohexylalanine or β-(cyclohexyl)-alanineCpa 3-(4-chlorophenyl)alanine Dab 2,4-diaminobutyric acid Dap2,3-diaminopropionic acid Dip 3,3′-diphenylalanine F5-Phe2,3,4,5,6-pentafluorophenyl]-alanine Fpa 4-fluorophenylalanine Gabaγ-aminobutyric acid or 4-aminobutyric acid HSer homoserine Igl2-indanylglycine Iph 4-iodophenylalanine Nal 3-(2-naphthyl)alanine Nlenorleucine Npa 4-nitrophenylalanine, or p-NO2-phenylalanine Nvanorvaline Pal 3-pyridylalanine or β-[3-pyridyl]-alanine Penpeniciliamine Pfp pentaflurophenylalanine Tba tert-butylalanine TfmTrifluoromethyl TfmA 4-trifluoromethylphenyl-alanine Thr(Bzl)O-benzyl-threonine Tic 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acidTle tert-leucine or α-[t-butyl]-glycine Tyr(Bzl) O-benzyl-tyrosineTyr(I) An iodinated tyrosine residue (e.g., 3-1-Tyr, 5-1-Tyr, 3,5-1-Tyr)wherein the iodine may be a radioactive isotope, e.g., I125, I127, orI131 Ypa 4-cyanophenylalanine *Abbreviations of the common amino acidsare in accordance with the recommendations of IUPAC-IUB *With theexception of the N-terminal amino acid, all abbreviations (e.g., Ala orA2) of amino acids in this disclosure stand for the structure of—NH—CH(R)—CO—, wherein R is a side chain of an amino acid (e.g., CH3 forAla). For the N-terminal amino acid, the abbreviation stands for thestructure of ═N—CH(R)—CO—, wherein R is a side chain of an amino acid.

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1. A method of controlling tight blood glucose levels comprisingadministering an effective amount of a somatostatin inhibitor to asubject in need thereof.
 2. The method of claim 1 for treating orpreventing hypoglycemia.
 3. The method of claim 1, wherein the subjectis an insulin-dependent diabetic.
 4. The method of claim 3, wherein thesubject has Type I diabetes.
 5. The method of claim 3, wherein thesubject has Type II diabetes.
 6. The method of claim 1, wherein thesubject suffers from idiopathic hypoglycemia.
 7. The method of claim 1,wherein the subject has an insulinoma tumor.
 8. The method of claim 1,wherein the somatostatin inhibitor is an antagonist of SSTR.
 9. Themethod of claim 8, wherein the somatostatin inhibitor is a peptideantagonist of SSTR or a pharmaceutically acceptable salt thereof. 10.The method of claim 8, wherein the somatostatin inhibitor is a peptideantagonist of SSTR2 or a pharmaceutically acceptable salt thereof. 11.The method of claim 8, wherein the somatostatin inhibitor is anantagonist of SSTR having a peptide as listed in peptide nos.: 27-436 ofTable 6 or a pharmaceutically acceptable salt thereof.
 12. The method ofclaim 8, wherein the somatostatin inhibitor is an antagonist of SSTRhaving a peptide as listed in peptide nos.: 27-120 of Table 6 or apharmaceutically acceptable salt thereof.
 13. The method of claim 8,wherein the somatostatin inhibitor is an antagonist of SSTR having apeptide sequence as shown in SEQ ID NOs:27-34 or a pharmaceuticallyacceptable salt thereof.
 14. The method of claim 8, wherein theantagonist of SSTR is the cyclic-octapeptide as shown in SEQ ID NO:28 ora pharmaceutically acceptable salt thereof.
 15. The method of claim 1,wherein the somatostatin inhibitor is an antisense nucleic acid of thesomatostatin nucleic acid sequence as shown in SEQ ID NO:15 or SEQ IDNO:16.
 16. The method of claim 1, wherein the somatostatin inhibitor isan antisense nucleic acid of a somatostatin receptor nucleic acidsequence as shown in any one of SEQ ID NOs: 17-26.
 17. The method ofclaim 1, wherein the somatostatin inhibitor is an antisense nucleic acidof the somatostatin receptor 2 nucleic acid sequence as shown in SEQ IDNO: 19 or SEQ ID NO:20.
 18. The method of claim 1, wherein thesomatostatin inhibitor is an antibody against a somatostatin or asomatostatin receptor.
 19. The method of claim 18, wherein the antibodyagainst the somatostatin binds to a somatostatin protein having theamino acid sequence as shown in any one of SEQ ID NOs:1-4.
 20. Themethod of claim 18, wherein the antibody against the somatostatinreceptor binds to a somatostatin receptor having the amino acid sequenceas shown in any one of SEQ ID NOs:5-14.
 21. The method of claim 18,wherein the antibody against the somatostatin receptor binds to asomatostatin receptor 2 having the amino acid sequence as shown in SEQID NO:7 or SEQ ID NO:8.
 22. The methods of claim 1, wherein the subjectis a mammal.
 23. The method of claim 22, wherein the subject is human.24. The method of any one of claim 1, wherein the subject has any bloodglucose level.
 25. The method of claim 1, wherein the subject has ablood glucose level of less than 4.0 mM.